C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful derivatives, coupling strategies

Article abstract of DOI:10.1007/s00726-016-2346-5

To obtain key sugar derivatives for making homooligomeric foldamers or α/β-chimera peptides, economic and multigram scale synthetic methods were to be developed. Though described in the literature, the cost-effective making of both 3-amino-3-deoxy-ribofuranuronic acid (H–tX–OH) and its C-3 epimeric stereoisomer, the 3-amino-3-deoxy-xylofuranuronic acid (H–cX–OH) from d-glucose is described here. The present synthetic route elaborated is (1) appropriate for large-scale synthesis; (2) reagent costs reduced (e.g. by a factor of 400); (3) yields optimized are ~80% or higher for all six consecutive steps concluding –tX– or –cX– and (4) reaction times shortened. Thus, a new synthetic route step-by-step optimized for yield, cost, time and purification is given both for d-xylo and d-ribo-amino-furanuronic acids using sustainable chemistry (e.g. less chromatography with organic solvents; using continuous-flow reactor). Our study encompasses necessary building blocks (e.g. –X–OMe, –X–OⁱPr, –X–NHMe, Fmoc–X–OH) and key coupling reactions making –Aaa–tX–Aaa– or –Aaa–tX–tX–Aaa– type “inserts”. Completed for both stereoisomers of X, including the newly synthesized Fmoc–cX–OH, producing longer oligomers for drug design and discovery is more of a reality than a wish.

Full text of DOI:10.1007/s00726-016-2346-5

Amino Acids
DOI 10.1007/s00726-016-2346-5
ORIGINAL ARTICLE
C‑3 epimers of sugar amino acids as foldameric building blocks:
improved synthesis, useful derivatives, coupling strategies
Adrienn Nagy1 · Barbara Csordás1 · Virág Zsoldos‑Mády2 · István Pintér1 ·
Viktor Farkas2 · András Perczel1,2
Received: 5 July 2016 / Accepted: 4 October 2016
© Springer-Verlag Wien 2016
Abstract To obtain key sugar derivatives for making
homooligomeric foldamers or α/β-chimera peptides, eco-
nomic and multigram scale synthetic methods were to be
developed. Though described in the literature, the cost-
effective making of both 3-amino-3-deoxy-ribofuranuronic
acid (H–tX–OH) and its C-3 epimeric stereoisomer, the
3-amino-3-deoxy-xylofuranuronic acid (H–cX–OH) from
d-glucose is described here. The present synthetic route
elaborated is (1) appropriate for large-scale synthesis; (2)
reagent costs reduced (e.g. by a factor of 400); (3) yields
optimized are ~80% or higher for all six consecutive steps
concluding –tX– or –cX– and (4) reaction times shortened.
Thus, a new synthetic route step-by-step optimized for
yield, cost, time and purification is given both for d-xylo
and d-ribo-amino-furanuronic acids using sustainable
chemistry (e.g. less chromatography with organic solvents;
using continuous-flow reactor). Our study encompasses
necessary building blocks (e.g. –X–OMe, –X–OiPr, –X–
NHMe, Fmoc–X–OH) and key coupling reactions making
–Aaa–tX–Aaa– or –Aaa–tX–tX–Aaa– type “inserts”. Com-
pleted for both stereoisomers of X, including the newly
synthesized Fmoc–cX–OH, producing longer oligomers for
drug design and discovery is more of a reality than a wish.
Keywords Sugar amino acids · Azido sugars ·
Nucleophilic substitution · Foldamers
Abbreviations
H-RibAFU(ip)-OH or tX 1,2-O-Isopropylidene-3-amino
-3-deoxy-α-d-ribofuranuronic
acid
H-XylAFU(ip)-OH or cX 1,2-O-Isopropylidene-3-amino
-3-deoxy-α-d-xylofuranuronic
acid
N3-RibAFU(ip)-OH
1,2-O-Isopropylidene-3-azido-
3-deoxy-α-d-ribofuranuronic
acid
N3-XylAFU(ip)-OH
H-XylAFU(ip)-NHMe
H-RibAFU(ip)-NHMe
Ac-RibAFU(ip)-NHMe
Ac-XylAFU(ip)-NHMe
1,2-O-Isopropylidene-3-azido-
3-deoxy-α-d-xylofuranuronic
acid
N-Methyl-1,2-O-isopro-
pylidene-3-amino-3-deoxy
-α-d-xylofuranuronamide
N-Methyl-1,2-O-
isopropylidene-3-amino-3-
deoxy-α-d-ribofuranuronamide
N-Methyl-1,2-O-
isopropylidene-3-acetamido-3-
deoxy-α-d-ribofuranuronamide
N-Methyl-1,2-O-
Handling Editor: J. Bode.
Electronic supplementary material The online version of this
article (doi:10.1007/s00726-016-2346-5) contains supplementary
material, which is available to authorized users.
* András Perczel
perczel@chem.elte.hu
1
Laboratory of Structural Chemistry and Biology, Institute
isopropylidene-3-
acetamido-3-deoxy-α-d-
xylofuranuronamide
of Chemistry, Eötvös Loránd University, Pázmány P. stny.
1/A, Budapest 1117, Hungary
2
MTA-ELTE Protein Modelling Research Group, Pázmány
P. stny. 1/A, Budapest 1117, Hungary
1 3

A. Nagy et al.
acids (β-SAAs) are generally soluble in water. Also they
would have similar conformational properties so they pre-
sent considerable synthetic challenges.
Introduction
Chimeric synthetic polypeptides composed of α/β-peptide
units are copolymers of emerging significance (Cheng et al.
2001; Horne and Gellman 2008; Pilsl and Reiser 2011;
Guichard and Huc 2011; Chandrasekhar et al. 2010; Kiss
and Fülöp 2014). Especially, those composed of functiona-
lized cyclobutane (Declerck and Aitken 2011; Gorrea et al.
2012; Pohl et al. 2013; Altmayer-Henzien et al. 2015),
cyclopentane (Martinek and Fülöp 2012; Rjabovs and
Turks 2013) and cyclohexane (Martinek and Fülöp 2012)
derivatives have biological importance and perspectives
(Cabrele et al. 2014; Mándity and Fülöp 2015). To a great
extent, the introduced non-natural amino acid derivatives
(e.g. ACPC, ACHC) contain the same number of torsional
angles (ϕ and ψ) as α-peptides do, two per residue; how-
ever, their backbone conformational behaviour is primarily
determined by local configurational properties. Reduced
mobility, if the conformation is carefully designed could
increase binding ability of the polypeptide to other macro-
molecules, receptors and thus enhance bioactivity.
Cis and trans stereoisomers of both 2-aminocyclopen-
tanecarboxylic acid (ACPC) and 2-aminocyclohexanecar-
boxylic acid (ACHC) derivatives are now extensively used
to design chimeras in conjunction with acyclic γ- and/or
δ-amino acid residues (Cabrele et al. 2014; Giuliano et al.
2013). However, as both ACPC and ACHC derivatives are
hydrophobic, their hydrophilic related compounds would
be of great relevance, not yet fully explored (Hetényi et al.
2009). Thus, their sugar analogues, called sugar amino
Amongβ-furanoidsugaraminoacids,1,2-O-isopropylidene-
3-amino-3-deoxy-α-d-ribofuranuronic acid (H-RibAFU(ip)-
OH, –tX–, 1) and its C-3 epimer, H-XylAFU(ip)-OH, (–cX–,
2) have attracted special attention (Fig. 1). The small-scale
synthesis of the N-protected derivatives of 1 and 2 from dia-
cetone-glucofuranose (3) was described in various quantities
(Gruner et al. 2001, 2002a, b; Chandrasekhar et al. 2004).
Conditions of these syntheses are different and the results are
sometimes poor.
Therefore, the ultimate goal of the present work was
to find an efficient and economical synthetic pathway of
multigram scale and high-yield preparation of both C-3
epimers (1 and 2) (Scheme 1). Key of this synthetic route is
the introduction of the –NH2 group, in other words making
the N-terminal of the amino acid at the C-3 carbon atom,
which is often a reduction following the sulfonate → azide
replacement.
The importance of these nucleophilic substitutions is
underlined by the review of Hale et al. (2015). This syn-
thetic problem is of a challenge and merits a careful evalu-
ation of the conditions. Consequently, the purpose of try-
ing various alternative routes using low-cost chemicals,
“greener” chemistry, giving higher yields is well-founded.
In addition, we have elaborated synthetic routes conver-
ting both azido uronic acids (6 and 7) into key derivatives
essential either for solid phase and in solution state peptide
chemistry (e.g. Boc-, Fmoc-) as well as preliminary co-
upling reactions were conducted making di- and triamide
nanosystems.
Therefore our primary interest was to make both H–tX–
OH and H–cX–OH β-sugar amino acids, as well as the fol-
lowing key derivatives needed for solid phase and/or solu-
tion state synthesis:
1. C-terminal temporarily protected residue (e.g. –tX–
OMe, –tX–OiPr),
2. the “next residue” mimicking C-terminal amide bond
(e.g. –cX–NHMe and –tX–NHMe),
Fig. 1 The two central key products applied for further syntheses are
H-RibAFU(ip)-OH (1, H-tX-OH) and H-XylAFU(ip)-OH (2, H-cX-
OH)
Scheme 1 General synthetic
pathway of 3-amino-3-deoxy-
pentofuranuronic acids (1 and
2) from diacetone-glucofura-
nose (3)
1 3

C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful…
Scheme 2 Synthesis of
1,2:5,6-di-O-isopropylidene-
3-azido-3-deoxy-d-allofuranose.
Reagents and conditions: a
Tf2O, Py, CH2Cl2; b MsCl,
Py; c NaH, DMF, Im2SO2; d
TsCl, Py; e NaN3, DMSO,
140–145 °C; f NaN3, DMSO,
Bu4NBr, 80 °C; g NaN3, DMF,
room temperature
3. N-terminal temporarily protected residue (e.g. Fmoc–
cX– and Fmoc–tX–) were made.
4. Finally “insert”, N3–tX–tX–NHMe was synthesized to
be ligated or elongated directly upon request.
compound 4 (A, B, C, D) and the 3-azido-3-deoxy-gluco
epimer 5 (E, F, G, H) (Schemes 2, 3) in multigram scale.
Application of known synthetic methods was combined
with reagent modification and yield optimization. By intro-
ducing mild reaction conditions, excluding column chroma-
tography when possible resulted in ways to use less organic
solvent and thus making our chemistry less polluting.
Results and discussion
In order to achieve our goal to find more efficient and eco-
nomical way for multigram scale synthesis of foldameric
intermediate product 1 and 2 starting from d-glucose via
diacetone-glucofuranose (3), the key step of the synthesis,
the sulfonate ester → azide replacement had to be opti-
mized. This transformation was performed earlier from
various sulphonate esters under different conditions and
in widely unlike scales. Consequently, one cannot find a
comparative estimate of the published data which would
establish the most reasonable and economic conditions for
the synthesis of either the 3-azido-3-deoxy-allofuranose
or the epimeric glucofuranose derivatives. In addition,
although the synthesis of the N-protected sugar amino acid
is described (Gruner et al. 2001, 2002a, b), the important
intermediate free sugar amino acid 1 was not yet isolated
and characterized.
(A) Synthesis of N3‑RibAFU(ip)‑OH (6)
and N3‑XylAFU(ip)‑OH (7)
Making 1,2:5,6-di-O-isopropylidene-3-azido-3-deoxy-α-d-
allofuranose (4) is the key step for which the sulfonate ester
(8, 9, 10, 11) → azide replacement (Scheme 2) had to be
achieved.
Following Gruner’s suggestions (Gruner et al. 2002b)
Route A via 3-O-trifluoromethanesulfonyl intermediate (8)
was found to be effective (≈16 h, T = 20 °C) as trifluo-
romethanesulfonate is an excellent leaving group. How-
ever, this approach has drawbacks and disadvantages: (1)
the reagent Tf2O is expensive and environment unfriendly;
(2) intermediate triflate (8) is unstable and thus, hard to
store. Route B via 3-O-methanesulfonyl intermediate (9)
was modified by carrying out in DMSO instead of DMF
(Ferreira et al. 2010). Compared to Tf2O, MsCl is a less
expensive reagent; however, the reactivity of mesylate 9
was lower requiring higher temperature and longer time
(≈181 h, T = 140 °C). In Route C via 3-O-toluene-sulfonyl
Hence, we accomplished alternative routes with differ-
ent sulfonate esters and under various reaction conditions,
then we evaluated the results to choose the most advanta-
geous protocol for producing both the 3-azido-3-deoxy-allo
1 3

A. Nagy et al.
Scheme 3 Synthesis of
1,2:5,6-di-O-isopropylidene-
3-azido-3-deoxy-d-glucofura-
nose. Reagents and conditions:
a (i) PCC, DCM; (ii) NaBH4,
EtOH-H2O or (i) TEMPO,
BAIB, DCM; (ii) NaBH4,
EtOH-H2O; b Tf2O, Py,
CH2Cl2; c MsCl, Py; d NaH,
DMF, Im2SO2; e TsCl, Py; f
NaN3, DMSO, 120 °C; g NaN3,
toluene, Bu4NBr, 80–90 °C; h
NaN3, DMSO, 135 °C
intermediate (10), Whistler’s work was modified (Nayak
and Whistler 1969), because we found that the reaction was
faster in DMSO. Reaction time (≈54 h, T = 140 °C) was
about one-seventh of the one published in DMF (360 h). In
some cases, the influence of catalysts (Bu4N-salts) or sol-
vent (DMSO–water) was investigated, but their effect was
found to be insignificant with respect to the overall yield.
Route D via 3-O-(N-imidazole-1-sulfonyl) derivative (11),
with modification of Vatéle’s work (Vatéle and Hanessian
1996), was carried out in DMSO instead of toluene and
resulted in better yield. The advantages of this route are
evident: (1) the reagent N,N’-sulfuryl-diimidazole is ea-
sily prepared and far less expensive than Tf2O; (2) the
intermediate 11 is a crystalline and very stable product; (3)
the formation of the azide 4 is fast (≈10 h, T = 80 °C) and
the yield is excellent (72%). The latter yield found as an
average after several repeats is higher than the one obtained
in Gruner’s experiment (A) and Vatéle’s works (Vatéle and
Hanessian 1996). The general problem of the above syn-
thetic routes starting from sulfonate intermediates of gluco
configuration (8, 9, 10, 11) is that the 3-O-sulfonate group
and the H-4 atom are in relative trans (antiperiplanar) posi-
tion. Thus, under nucleophilic conditions trans elimination
of the corresponding sulfonic acids cannot be prevented
and the result is the formation of the unsaturated side pro-
duct
1,2:5,6-di-O-isopropylidene-3-deoxy-α-d-erythro-
hex-3-enofuranose (12). The ratio of side product 12 varied
in total between 3 and 36% when syntheses were repeated.
The synthetic route yielding
isopropylidene-3-azido-3-deoxy-α-d-glucofuranose)
5
(1,2:5,6-di-O-
is
longer as two additional steps are needed when compared
with that making 4: transformation of diacetone-glucofura-
nose (3) into diacetone-allofuranose (13) via the inversion
of C-3 by oxido-reduction lengthens the protocol. Among
the tested oxidation methods, either oxidation with PCC,
or oxidation with TEMPO/BAIB was found to be the most
effective. The sulfonate → azide replacement was con-
ducted (Scheme 3) by using various 3-O-sulfonyl deriva-
tives, like the triflate (14), the mesylate (15), the tosylate
(16), and the imidazylate (17).
1 3

C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful…
Table 1 Yields and costs of the
synthesis of allofuranose (4)
and glucofuranose (5)
Compound
Reaction
route
Yield (%)
Price
Reaction time (h)
(USD)a
3-O-SO2R 3-N3
3-O-SO2R 3-N3
1,2:5,6-Di-O-isopropylidene-3-azido-
3-deoxy-α-d-allofuranose (4)
Ab
B
90
68
83
84
83
50
66
87
59
54
45
72
53
87
74
90
1600.00
2
16
181
54
14.50 48
21.00 24
4.00 1.5
C
D
10
1,2:5,6-Di-O-isopropylidene-3-azido-3- Ec
deoxy-α-d-glucofuranose (5)
1600.00
2
14.50 48
21.00 24
4.00 1.5
20
F
180
52
G
H
8
a
Prices of chemicals used for 0.5 mol of starting material (3 and 13) (from the catalogue of Sigma-Aldrich
2016)
b
Synthesis performed by modifying the reported protocol (Gruner et al. 2002b). This result served as pri-
mary standard for the comparison of other cases
c
Synthesis performed by modifying the reported protocol (Austin et al. 1987). This result served as pri-
mary standard for the comparison of other cases
The reactions with 14, 15 and 16 were carried out with
modification of the earlier described methods (Ferreira
et al. 2010; Austin et al. 1987), by using DMSO instead
of DMF. Although the 3-O-imidazole-sulfonate ester 17
was known in the literature, its transformation into 5 has
not been earlier executed. In Route H compound 17 gave
the main product 5 with excellent yield, also in multigram
scale.
In summary, comparison of the yields of the allo com-
pound 4 with those of the gluco compound 5 points out that
data were higher for the latter almost in all cases. The main
reason is that in the gluco sulfonate esters the configura-
tion of the C-3 is opposite to that of allo derivatives. Hence,
structural conditions for the elimination reaction producing
unsaturated 12 are not given. In Table 1 the effectiveness
of the various synthetic paths for the azides 4 and 5 are
compared.
In conclusion, Routes B and C are less expensive ways
than Route A, however, due to the low yield and the long
reaction time, they are not good alternatives. Following
Route D via 3-OIms derivative (11) both costs (<1/400th)
and reaction time (10 h ≈ 2/3) can be lowered signifi-
cantly; moreover, yield turned out to be excellent (72%)
and thus this is the method of choice, appropriate for large-
scale synthesis (Table 1). Similarly, Route H via 3-OIms
derivative (17) was found to be the most suitable one for
large-scale synthesis of 5, as both cost (1/400th) and reac-
tion time (8 h ≈ 2/5) are lower than that of Route E of the
described alternative (Austin et al. 1987). In addition, yield
was almost excellent (90%) (Table 1). In addition, Route
H avoids the use of the environment unfriendly Tf2O and
introduced an easily isolable and stable intermediate 17.
Substituent effect of C‑4 on the 3‑O‑sulfonate → azide
replacement reaction
In all cases of sulfonate → azide replacement the yield of
the 3-azido-3-deoxy-allofuranose product (4) was influ-
enced by the trans elimination of the different sulfonic
acid derivatives under basic conditions: furnishing the
undesired 3,4-unsaturated derivative 12 (Watterson et al.
1999). The chance of the trans elimination is controlled
by the partial positive charge of H-4, determined by elec-
tronic and/or steric effect of the substituent at C-4 due to
its proximity to the reaction centre. To elucidate this influ-
ence we compared the reaction of six derivatives having
three different substituents at C-4. During the removal of
the 5,6-O-isopropylidene protecting group of 3-O-(N-imi-
dazole-1-sulfonyl) derivative (11) unexpected synthetic
challenges occurred (Szaniszló et al., to be published), the
reaction with the 3-O-toluene-sulfonyl intermediate (10) is
discussed here.
The –OTs → –N3 replacement reactions of gluco
derivative 1,2:5,6-di-O-isopropylidene-3-O-sulfonate (10,
Scheme 4) and the derived partially unprotected 1,2-O-iso-
propylidene-3-O-sulfonate (18) yield the target 3-azido-
3-deoxy compounds (4 and 19) and the 3,4-unsaturated
side products (12 and 20) similarly. Thus, in both cases the
steric effect determines the product primarily. In contrast
to this, starting from 21 the exclusive formation of the cor-
responding unsaturated side product 22 (90%) is explained
by the strong electron withdrawing effect of –COOCH3
group, remarkably increasing the partially positive charge
of H-4. In the parallel reactions of the corresponding allo
derivatives (16, 23 and 24) the relative cis configuration
1 3

A. Nagy et al.
Scheme 4 Competing substitution and elimination reaction for 3-O-tosylates. Reagents and conditions: a NaN3, DMSO, 135–145 °C; b AcOH–
H2O 3:1; c NaIO4, MeOH; d KMnO4, AcOH–H2O 1:1; e CH2N2/Et2O, DCM; f NaN3, DMSO, 80 °C
Scheme 5 Synthesis of
N3-RibAFU(ip)-OH and
N3-XylAFU(ip)-OH. Reagents
and conditions: a AcOH–
H2O 3:1; b NaIO4, MeOH; c
KMnO4, AcOH–H2O 1:1
of substituents at C-3 and C-4 gives no a priori possibi-
lity of the trans elimination. The expectation fulfilled both
for 16 and 23, where no 3,4-unsaturated side products were
detected. At the same time, ester 24 afforded exclusively
the 3,4-unsaturated compound 22 (92%) also isolated from
the similar reaction of 21. The reason for this feature is the
electronic effect of –COOCH3 group is sufficiently strong
to induce the cis elimination of toluenesulfonic acid, gi-
ving 22 as the main product. Hence, 3-O-sulfonate → azide
replacement for both gluco and allo series is advanta-
geously executed at the beginning of the reaction pathway,
preferably on 1,2:5,6-di-O-isopropylidene compounds.
The formation of the unsaturated by-product 12
brings with the technical difficulty of its separation
from the main product 4. The column chromatography
used by Vatéle and Hanessian (1996) was an appropriate
choice for small quantities such as 300 mg, but not when
synthesis is made on a larger scale. Therefore, we have
reconsidered the purification process and have developed
the following alternative working up, clearly more eco-
nomic and environmentally friendly. The rough pro-
duct was treated with KMnO4 to oxidize the unsaturated
by-product 12 into a vicinal diol and the water-soluble
derivative easily extracted into the water phase. This
improvement omitted the use of any chromatography
(see “Methods”).
Transformation of gluco and allo 3‑azido‑3‑deoxy
intermediates (4 and 5) into N3‑RibAFU(ip)‑OH
and N3‑XylAFU(ip)‑OH
Selective removal of 5,6-O-isopropylidene protecting
group of both trans and cis intermediates (4 and 5) with the
conventional procedure (Zsoldos-Mády and Zbiral 1986)
resulted in the 5,6-dihydroxy derivatives (19 and 25). After
oxidative cleavage of diol compounds with sodium meta-
periodate, the oxidation of the aldehydes was in situ per-
formed into the carboxylic acids 6 and 7 (Scheme 5).
1 3

C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful…
Scheme 6 The ultimate simplified reaction route to make azido-furanuronic acids as foldameric building blocks. Used reagents: a Im2SO2; b
NaN3; c AcOH; d NaIO4 and KMnO4
Scheme 7 Synthesis of AFU diamides for both C-3-epimers. Reagents and conditions: a (i) oxalyl chloride, DMF, THF, (ii) 2 M MeNH2/THF;
b (i) ClCOOiBu, Et3N, DMF, (ii) 2 M MeNH2/THF; c H-Cube® H2, CH3OH, 10% Pd/C; d Ac2O–pyridine
In conclusion, in line with Scheme 6 we propose the
following reaction route, all steps now optimized using
reagents of low costs, with unavoidable side products
repressed and/or eliminated.
Ac-XylAFU(ip)-NHMe (27), the simplest and smallest
models of homo- and heterooligomers of peptides (Per-
czel et al. 1991; James et al. 2009; Knapp et al. 2014). Both
3-azido-3-deoxy-furanuronic acids (6 and 7) are adequate
intermediates for the synthesis of 26 and 27, respectively,
standing for β-amino acids with amide bonds at both ends
(Scheme 7).
(B) Preparation of β‑amino acid model compounds
as LEGO‑type bricks for foldamer research field
N-Methyl-carboxamide moiety was formed from both 6
and 7 with conventional amidation methods. Reduction of
the azido group was carried out in an H-Cube® reactor with
Pd/C, resulting in amino compound 28 and 29 in excellent
yield (85–95%).
Interesting to note that by using the Staudinger reaction
severe synthetic difficulties were observed, namely with
the xylo(cis) epimer (30) the failure of the hydrolysis of
the unexpectedly stable phosphinimine was observed. The
rational explanation of the unexpected stability was found
in steric repulsions and electronic interactions caused by
the relative cis position of the vicinal triphenylphosphini-
mino group at C-3 and the substituents of C-4. These struc-
tural conditions were established by 3D-NMR and X-ray
diffraction studies and corroborated by DFT calculations
(Csordás et al. 2016).
The 3-azido group of compounds 6 and 7 was reduced on
two alternative ways: (a) hydrogenation in H-Cube® with
Pd/C; (b) transformation via iminophosphorane (Ph3P=N–)
under the conditions of Staudinger reaction and subsequent
hydrolysis (Csordás et al. 2016). Advantages of the use of
H-Cube® continuous-flow reactor instead of the traditional
catalytic hydrogenation are the higher yield and the easier
separation of the product.
As mentioned earlier H-AFU-OH derivatives might be
significant in peptide–foldamer sciences. The appropri-
ate reaction conditions of peptide bond formation with
H-AFU-OH are depending both on structure and substitu-
ents of the β-SAAs. Both N-acylation and N(Me)-amide
formation reactions were tested on our AFUs (1 and 2) gi-
ving either Ac-RibAFU(ip)-NHMe (26) or the xylo epimer
1 3

A. Nagy et al.
acids as building block is essential. Thus, we have synthe-
sized Fmoc-protected derivatives of –X– by using a continu-
ous-flow hydrogenation reactor and subsequently Fmoc-OSu
reagent (Scheme 9). At present Boc-protection is unsuitable
as both Boc- and 1,2-O-isopropylidene group is acid labile.
The yields of hydrogenation are good (>80%), by using
a continuous-flow reactor, a method fast, economic, useful
and environmentally friendly. The subsequent reaction with
Fmoc-OSu was found to perform poorer: the N-protected
Fmoc-products were of moderate yield (51–49%). Never-
theless, in this way both Fmoc-RibAFU(ip)-OH (33) and
its stereoisomer Fmoc-XylAFU(ip)-OH (34) are made, the
former one synthesized for the first time. Thus, both Fmoc-
key intermediates of AFU are now available for SPPS.
Scheme 8 Coupling of sterically hindered trans-β-furanoid SAA
dipeptide, namely N3-RibAFU(ip)-RibAFU(ip)-NHMe. Reagents and
conditions: a ClCOOiBu, Et3N, DMF, −15 °C
Coupling trans AFU derivatives making new β‑peptide
derivative (32)
Foldamer synthesis with sterically hindered amines is a
challenge and thus, preliminary reaction in optimizing
conditions for making short sequences from β-amino acids
is a requirement: dimeric, tetrameric and hexameric units
form some of them were already studied (Chandrasekhar
et al. 2004, 2005, 2008; Jagannadh et al. 2006; Pandey
et al. 2011; Giri et al. 2012; Threlfall 2008). Here, we pre-
sent the synthesis of N-terminal “masked”, C-terminal pro-
tected -X-X- type β-dipeptide, by coupling N-methylated
3-amino-3-deoxy-ribofuranuronamide (28) with the related
3-azido-3-deoxy-ribofuranuronic acid (6, Scheme 8). The
use of compound 6 as a reaction partner is based on the
scope of the azido group being indeed a robust and uniform
“mask” of the -NH2 functionality, hence, it might play the
role of both Fmoc-NH and Boc-NH functions widely used
in peptide synthesis.
Conclusion
As we established, the success of the 6(7) stepped synthesis
of β-sugar amino acids, as 3-amino-3-deoxy-pentofuranu-
ronic acids (1 and 2) depends strongly on the efficacy of
the transformation of the key step of 3-O-sulfonyl ester into
the 3-azido-3-deoxy derivative. From d-glucose, the most
abundant carbohydrate source, both C-3 epimers of the
azido-furanuronic acid of both d-ribo and d-xylo configura-
tion were obtained within 6(7) consecutive reaction steps.
Yields are now optimized, only scalable and robust reac-
tions are used. With detailed experimental studies on vari-
ous fully protected 3-O-sulfonyl-furanoses we have estab-
lished optimum conditions forming key intermediates and
derivatives. As described recently (Pandey et al. 2011; Giri
et al. 2012), newly synthesized sugar amino acid deriva-
tives including the herein reported Fmoc–X–, key reac-
tions and intermediates of the sterically hindered secondary
amines were probed to make successfully –Aaa–tX–Aaa–
and –Aaa–tX–tX–Aaa– type “inserts” for α/β-chimera
peptides. Thus, we have shown that both C-3 epimers of
3-azido-3-deoxy-pentofuranuronic acid, N3-RibAFU(ip)-
OH (6) and N3-XylAFU(ip)-OH (7) are suitable building
blocks to be inserted into β/β-oligopeptides. Making N3-
RibAFU(ip)-RibAFU(ip)-NHMe (32) is still a challenge
due to steric hindrance, a step to be improved (Fig. 2).
Coupling was carried out in solution under the usual
conditions of peptide bond formation and the expected
β-dipeptide (32) was isolated and purified. Though the
yield is poor and needs to be improved and optimized, it
is important that –tX-tX– can be achieved, thus direct co-
upling is possible.
Synthesis of N‑protected building block for SPPS
In modern peptide chemistry, the development of synthetic
routes for the access of new N-protected monomeric amino
Scheme 9 Synthesis of Fmoc-protected β-amino acid derivatives (Fmoc-RibAFU(ip)-OH and Fmoc-XylAFU(ip)-OH) for solid phase peptide
synthesis. Reagents and conditions: a H-Cube® H2, CH3OH, 10% Pd/C, b MeOH-H2O 2:1, NaHCO3, Fmoc-OSu/THF
1 3

C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful…
Experimental section
Methods
Reagents, starting materials and solvents were obtained
from Sigma-Aldrich, Merck, Reanal and VWR. Mois-
ture-sensitive solvents either were distilled as standard
procedure or dried on molecular sieve. Column chro-
matography was performed on Kieselgel 60 silica gel
(0.040–0.063 mm; Merck). Reactions were monitored
by thin-layer chromatography on Kieselgel 60 F254 (E.
Merck). The plates were developed by UV-detection
(254 nm) and charring with aqueous sulfuric acid solu-
tion. Melting points were defined with a Boetius micro-
scope apparatus. MS spectra were performed with Bruker
Esquire 3000+ tandem quadrupole mass spectrometer
equipped with an electrospray ion source. FTIR spectra
were recorded on a Bruker IFS 28 spectrometer by ATR
1
technique. H-NMR spectra were measured with Bruker
Avance 250 spectrometer in CDCl3, D2O, DMSO-d6 at
room temperature. Deuterated solvents were purchased
from Sigma-Aldrich.
1,2:5,6‑Di‑O‑isopropylidene‑α‑d‑glucofuranose (3)
From α-d-glucose (100.0 g; 0.55 mol) with Schmidt’s
method (Schmidt 1963). The product 3 formed white crys-
tals (79.8 g; 55%). M. p.: 112–113 °C; lit. m.p. (Schmidt
1963): 110 °C; Rf = 0.74 (hexane–EtOAc 1:2).
1,2:5,6‑Di‑O‑isopropylidene‑α‑d‑allofuranose (13)
Fig. 2 Selected key Lego modules of water-soluble β-sugar amino
acids, 6 and 7 made resourcefully from D-Glc
(I) From 3 (5.0 g; 0.02 mol) with Austin’s method (Austin
et al. 1987), the product 13 formed white crystals (3.3 g;
67%). M.p.: 75–77 °C; lit. m.p. (Austin et al. 1987):
77–78 °C; Rf = 0.57 (hexane–EtOAc 1:1).
These ones and similar compounds are expected to be
important intermediates both for academic research as
well as for manufacturing biocompatible nanomaterials.
The herein presented synthetic route was selected in line
with sustainable or green(er) chemistry (e.g. most chro-
matography with organic solvents eliminated, continuous-
flow reactor used for hydrogenation, highly toxic reagents
replaced), by using the more economic azide intermediates
when possible and thus, shortened by two reaction steps.
All at a lower cost, derivatives now available on multigram
scale, products obtained at a shorter time. Encompassing
most necessary building blocks also tested in key coupling
reactions for both stereoisomers of X gives “pros and cons”
of the route to be selected for further optimization of co-
upling strategies and conditions in making longer oli-
gomers perhaps ligated into polypeptides, chimera and
foldamers.
(II) 1,2:5,6-Di-O-isopropylidene-α-d-glucofuranose (3)
(5.0 g; 0.02 mol) was dissolved in DCM (20 ml) then TEMPO
(0.75 g; 4.7 mmol; 0.25 eqv.) and BAIB (2.5 eqv.) were
added in several portions. The reaction mixture was stirred
for 2 days at room temperature. The solution was diluted with
DCM (100 ml) and washed with saturated Na2S2O3 solution
(2 × 50 ml). The aqueous phase was extracted with DCM
(5 × 50 ml). The organic phase was washed with saturated
NaHCO3 solution (2 × 50 ml) and brine (2 × 50 ml). The
combined organic extracts were dried (Na2SO4), filtered and
concentrated in vacuo. The crude ketone was transformed
without any isolation and purification. The reduction was car-
ried out as in the case of method (A). The crude material was
purified with column chromatography (hexane–EtOAc 1:1)
to give the pure product 13 (2.6 g; 52%).
1 3

A. Nagy et al.
Synthesis of 3‑O‑sulfonate derivatives
and Meyer 1968): 130–133 °C; Rf = 0.44 (hexane–EtOAc
1:1).
1,2:5,6‑Di‑O‑isopropylidene‑3‑O‑toluenesulfonyl‑α‑d‑glu‑
cofuranose (10)
1,2:5,6‑Di‑O‑isopropylidene‑3‑O‑trifluoromethanesul‑
fonyl‑α‑d‑glucofuranose (8)
(I) 1,2:5,6-Di-O-isopropylidene-α-d-glucofuranose (3)
(3.9 g; 15.0 mmol) was dissolved in dry pyridine (15 ml)
and p-toluenesulfonyl chloride (5.7; 29.9 mmol) was added
to the solution with stirring at room temperature. The sus-
pension was stirred for 1 day and allowed to stand for over-
night at 0 °C. The reaction mixture was poured into ice-
water, the precipitate was filtered, washed with cold water.
The cream-coloured crude material was recrystallized from
ethanol (95%) to give white crystalline product 10 (5.1 g;
83%). M.p.: 125–127 °C; lit. m.p. (Whistler and Doner
1972): 122–123 °C; Rf = 0.80 (hexane–EtOAc 2:1).
1,2:5,6-Di-O-isopropylidene-α-d-glucofuranose (3) (3.0 g;
0.01 mol) was dissolved in dichloromethane (30 ml) con-
taining pyridine (2.8 ml). The reaction mixture was cooled
at −10 °C and under N2-atmosphere trifluoromethanesul-
fonic anhydride (2.9 ml) was dropped to the solution. The
reaction mixture was stirred for 2 h. After the solution was
poured into ice-water, the aqueous phase was extracted
with dichloromethane. The organic phase was dried
(Na2SO4), filtered and concentrated in vacuo. The white
crystalline product 8 crystallized from n-hexane (4.1 g;
90%). M.p.: 76–77 °C; lit. m.p. (Hall and Miller 1976):
70 °C; Rf = 0.61 (hexane–EtOAc 1:2).
(II) From 3 (19.5 g; 75.0 mmol) the yield was 81% (25.1 g).
1,2:5,6‑Di‑O‑isopropylidene‑3‑O‑toluenesulfonyl‑α‑d‑
allofuranose (16)
1,2:5,6‑Di‑O‑isopropylidene‑3‑O‑trifluoromethanesul‑
fonyl‑α‑d‑allofuranose (14)
(I) From 1,2:5,6-di-O-isopropylidene-α-d-allofuranose
(13) (10.0 g; 38.0 mmol) the reaction was carried out with
the same method as the formation of 10. After recrystal-
lization of the crude product from ethanol (90%) the pro-
duct 16 was obtained as white crystals (6.3 g; 63%). M.p.:
118–120 °C; lit. m.p. (Theoneste et al. 2009): 116–118 °C;
Rf = 0.64 (hexane–EtOAc 1:1).
From 1,2:5,6-di-O-isopropylidene-α-d-allofuranose (13)
(0.50 g; 2.0 mmol) the reaction was carried out with the
same method as the formation of 8. The product 14 was
pale yellow syrup (0.62 g; 83%). Rf = 0.38 (hexane–EtOAc
4:1).
(II) From 13 (19.5 g; 75.0 mmol) the yield was 66%
(20.5 g).
1,2:5,6‑Di‑O‑isopropylidene‑3‑O‑(N‑imidazole‑1‑sulfonyl)
‑α‑d‑glucofuranose (11)
1,2:5,6‑Di‑O‑isopropylidene‑3‑O‑methanesulfonyl‑α‑d‑
glucofuranose (9)
(I) 1,2:5,6-Di-O-isopropylidene-α-d-glucofuranose (3)
(1.0 g; 4.0 mmol) was dissolved in DMF (20 ml), cooled
at 0 °C and under N2-atmosphere NaH (0.14 g; 6.0 mmol)
was added to the solution. The suspension was stirred for
30 min and cooled to −35 to −40 °C. After N′,N-sulfonyl-
diimidazole (1.2 g; 6.0 mmol) in DMF (12 ml) was dropped
to the reaction mixture and stirred for 30 min again at
−40 °C. MeOH was added (0.8 ml) to the solution and
stirred for 30 min at −40 °C. The solution was poured into
ice-water (200 ml). The precipitate was filtered, washed
with cold water to get the white crystalline product 11
(1.2 g; 80%). M.p.: 97–98 °C; lit. m.p. (Vatéle and Hanes-
sian 1996): 98–99 °C; Rf = 0.70 (EtOAc–hexane 1:1).
(II) From 3 (25.0 g; 96.0 mmol) the yield was 84% (31.5 g).
1,2:5,6-Di-O-isopropylidene-α-d-glucofuranose (3) (2.0 g;
7.7 mmol) was dissolved in dry pyridine (6 ml), cooled at
0 °C and methanesulfonyl chloride (0.8 ml) was dropped
to the solution. The reaction mixture was allowed to stand
for 2 days at 0 °C. After the solution was poured into ice-
water, the solid crude product was filtered, washed with
cold water and recrystallized from methanol (50%) to give
white crystalline product 9 (1.8 g; 68%). M.p.: 83–84 °C;
lit. m.p. (Helferich et al. 1939): 83–84 °C; Rf = 0.44 (hex-
ane–EtOAc 2:1).
1,2:5,6‑Di‑O‑isopropylidene‑3‑O‑methanesulfonyl‑α‑d‑al‑
lofuranose (15)
1,2:5,6‑di‑O‑isopropylidene‑3‑O‑(N‑imidazole‑1‑sulfonyl)‑
α‑d‑allofuranose (17)
From 1,2:5,6-di-O-isopropylidene-α-d-allofuranose (13)
(0.50 g; 1.9 mmol) the reaction was carried out with the
same method as the formation of 9. Recrystallization of the
crude product from ethanol gave white crystalline product
15 (0.32 g; 50%). M.p.: 133–136 °C; lit. m.p. (Reckendorf
(I) From 1,2:5,6-di-O-isopropylidene-α-d-allofuranose
(13) (1.0 g; 4.0 mmol) the reaction was carried out with
the same method as the formation of 11, but after the solu-
tion was poured into ice-water, the aqueous phase was
1 3

C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful…
extracted with diethyl ether (4 × 60 ml). The combined
organic extracts were washed with water (4 × 30 ml) to
pH 7. The organic phase was dried (MgSO4), filtered and
concentrated in vacuo to give colourless oil (1.4 g; 87%).
Rf = 0.40 (EtOAc–hexane 1:1); ESI-MS: 391.2 [M+H]+,
calculated: 390.4 m/z.
(Na2SO4), filtered and concentrated in vacuo to afford the
crude product, which was the mixture of 4 and the by-pro
duct 12. The crude product was purified by column chroma-
tography (hexane–EtOAc 4:1, 3:1). The product 4 was co
lourless oil (0.26 g; 41%). The by-product 12 formed white
crystals (0.02 g; 3%). Spectral and chromatographic data of
the products are in agreement with the data of the products
by (A).
(II) From 13 (25.0 g; 96.0 mmol) the yield was 80%
(30.0 g).
(C): (II) From 10 (25.1 g; 60.6 mmol) the yield was 45%
(7.8 g) for 4 and 8% (1.2 g) for 12.
Sulfonate ester → azide SN‑reaction
(C): (III) From 10 (0.41 g; 1.0 mmol) the reaction occurred
analogously to method (C): (I), with sodium azide (4 eqv.)
and catalytic amount of tetra-N-butylammonium hydrogen-
sulfate (0.006 eqv.) was added to the solution. The reaction
mixture was stirred at 140–145 °C for 33 h. The product 4
was colourless oil (0.09 g; 44%), the by-product 12 formed
white crystals (0.01 g; 7%). Spectral and chromatographic
data of the products are in agreement with the data of the
products by (A).
(C): (IV) From 10 (24.1 g; 58.1 mmol) the reaction
occurred analogously to method (C): (I), with tetra-N-bu-
tylammonium chloride (0.006 eqv.) catalyst. The reaction
mixture was stirred at 130–135 °C for 73 h. The crude
product was purified by column chromatography (hexane–
acetone 14:1). The product 4 was colourless oil (5.4 g;
33%), the by-product 12 formed white crystals (1.5 g;
11%). Spectral and chromatographic data of the products
are in agreement with the data of the products by (A).
(C): (V) From 10 (25.0 g; 60.3 mmol) the reaction occurred
analogously to method (C): (I), in DMSO–H2O 96:4. The
crude product was purified by flash chromatography (hex-
ane–acetone 14:1). The yield for 4 was 37% (6.3 g) and for
12 was 7% (1.1 g). Spectral and chromatographic data of
the products are in agreement with the data of the products
by (A).
1,2:5,6‑Di‑O‑isopropylidene‑3‑azido‑3‑deoxy‑α‑d‑allofu‑
ranose (4)
(A)1,2:5,6-Di-O-isopropylidene-3-O-trifluoromethanesulfo
nyl-α-d-glucofuranose (8) (0.56 g; 1.4 mmol) was dissolved
in DMF (25.5 ml). Sodium azide (0.19 g; 2.9 mmol; 2 eqv.)
and catalytic amount of tetra-N-butylammonium hydrogen-
sulfate (0.002 g; 0.006 mmol) were added to the solution
and stirred at 50 °C for 3 h and at room temperature for
13 h. The reaction was followed by TLC (hexane–EtOAc
3.5:1). The reaction mixture was concentrated in vacuo,
the residue was dissolved in EtOAc (20 ml) and extracted
with water (2 × 5 ml). The aqueous phase was extracted
with EtOAc (3 × 3 ml). The combined organic extracts
were dried (MgSO4), filtered and concentrated in vacuo to
afford the crude product, which was the mixture of 4 and
12. The crude product was purified by flash chromatogra-
phy (hexane–EtOAc 3.5:1, 3.2:1, 2.5:1). The product 4 was
colourless oil (0.18 g; 59%). Rf = 0.53 (hexane–EtOAc
3:1); FTIR-ATR: νmax: 2106 (ν N3) cm−1. The by-product
12 formed white crystals (0.09 g; 36%). M.p.: 49–50 °C;
lit. m.p. (Whistler and Doner 1972): 51 °C; Rf = 0.75 (hex-
ane–EtOAc 3:1); FTIR-ATR: νmax: 1672 (ν C=C) cm−1
.
(B) 1,2:5,6-Di-O-isopropylidene-3-O-methanesulfonyl-α-
d-glucofuranose (9) (0.34 g; 1.0 mmol) was dissolved in
DMSO (8 ml). Sodium azide (0.59 g; 9.0 mmol; 9 eqv.)
was added to the solution and stirred at 140–145 °C for
181 h. The processing of the reaction mixture was analo-
gous to the above. The crude product was homogeneous
containing only the main product 4, so further purifica-
tion was not necessary. The product 4 was colourless oil
(0.12 g; 54%). Spectral and chromatographic data of the
product is in agreement with the data of the product by (A).
(C): (I) 1,2:5,6-Di-O-isopropylidene-3-O-toluenesulfonyl-
α-d-glucofuranose (10) (1.2 g; 3.0 mmol) was dissolved in
DMSO (33 ml). Sodium azide (1.2 g; 18.0 mmol; 6 eqv.)
was added to the solution and stirred at 140–145 °C for
54 h. The reaction was followed by TLC (hexane–EtOAc
3.5:1). The reaction mixture was poured into ice-water
(250 ml), extracted with petroleum ether (6 × 15 ml) and
with ethyl acetate (2 × 15 ml). The combined organic
extracts were washed with brine (1 × 20 ml), dried
(D): (I) 1,2:5,6-Di-O-isopropylidene-3-O-(N-imidazole-
1-sulfonyl)-α-d-glucofuranose (11) (1.1 g; 2.8 mmol) was
dissolved in toluene (33 ml). Tetra-N-butylammonium
bromide (2.7 g; 8.4 mmol; 3 eqv.) and NaN3 (0.55 g;
8.5 mmol; 3 eqv) were added to the solution and stirred for
30 min at room temperature. After the reaction mixture was
refluxed for 10 h at 80 °C. The reaction was followed by
TLC (EtOAc–hexane 1:1). After the reaction was complete,
KMnO4 solution (0.45 g; 1 eqv.) was added to the reaction
mixture and stirred for 5 h. The organic phase, which con-
tained only the main product 4 was separated and washed
with water (2 × 10 ml). The combined organic extracts
were dried (Na2SO4), filtered and concentrated in vacuo to
afford the product 4 as colourless oil (0.42 g; 52%). Spec-
tral and chromatographic data of the product are in agree-
ment with the data of the product by (A).
(D): (II) From 11 (31.5 g; 80.8 mmol) the yield was 62%
(14.3 g).
1 3

A. Nagy et al.
(D): (III) From 11 (0.3 g; 0.77 mmol) the reaction was
analogous with method (D): (I), but the solvent was DMSO
instead of toluene and the crude product, which was the
mixture 4 and 12 was purified by column chromatography
(hexane–acetone 14:1). The yield was 72% (0.16 g) for 4
and 20% (0.04 g) for 12.
1,2‑O‑Isopropylidene‑3‑azido‑3‑deoxy‑α‑d‑allofuranose
(19)
1,2-O-Isopropylidene-3-O-toluenesulfonyl-α-d-glucofuranose
(18) (0.50 g; 1.3 mmol) was dissolved in DMSO (1.8 ml).
Sodium azide (0.35 g; 5.2 mmol; 4 eqv.) in DMSO (9.4 ml)
was dropped to the solution and stirred at 135 °C for 29 h. The
reaction mixture was poured into ice-water (15.0 ml), extracted
with ethyl acetate (7 × 3 ml) and the combined organic
extracts were washed brine (1 × 5 ml), dried (Na2SO4), fil-
tered and concentrated in vacuo to afford the crude product,
which was the mixture of the main product 19 and the elimi-
nation by-product 20. The crude product was purified by col-
umn chromatography (EtOAc–hexane 2:1). The product 19
formed white crystals (0.11 g; 36%). M.p.: 76–78 °C; lit. m.p.
(Gomtsyan et al. 1992): 75–76 °C; Rf = 0.54 (EtOAc); FTIR-
ATR: νmax: 3500 and 3358 (ν OH), 2100 (ν N3) cm−1. The by-
product 20 is yellow oil (0.006 g; 2%).
1,2:5,6‑Di‑O‑isopropylidene‑3‑azido‑3‑deoxy‑α‑d‑
glucofuranose (5)
(E) From 1,2:5,6-di-O-isopropylidene-3-O-trifluoromethane
sulfonyl-α-d-allofuranose (14) (0.56 g; 1.4 mmol) was
dissolved in DMSO (25.5 ml). Sodium azide (0.48 g;
7.3 mmol; 5 eqv.) and catalytic amount of tetra-N-bu-
tylammonium hydrogensulfate (0.002 g; 0.006 mmol) were
added to the solution and refluxed at 120 °C for 20 h. The
reaction was followed by TLC (hexane–EtOAc 3.5:1),
cooled at room temperature and streamed to ice-water
(100 ml). The solution was extracted with petroleum ether
(8 × 20 ml) and the combined organic extracts were washed
with brine (3 × 20 ml), dried (MgSO4), filtered and con-
centrated in vacuo to afford a golden yellow oil. The crude
product was purified by column chromatography (hex-
ane–EtOAc 3.5:1) to give a light yellow oil (0.16 g; 53%).
Rf = 0.83 (EtOAc–hexane 1:1); FTIR-ATR: νmax: 2111 (ν
1,2‑O‑Isopropylidene‑3‑azido‑3‑deoxy‑α‑d‑glucofuranose
(25)
1,2-O-Isopropylidene-3-O-toluenesulfonyl-α-d-allofuranose
(23) (0.50 g; 1.3 mmol) was dissolved in DMSO (1.8 ml).
Sodium azide (0.52 g; 7.9 mmol; 6 eqv.) in DMSO (9.4 ml)
was dropped to the solution and stirred at 135 °C for 28 h.
The reaction mixture was poured into ice-water (15.0 ml),
extracted with ethyl acetate (6 × 3 ml) and the combined
organic extracts were washed with brine (1 × 5 ml), dried
(Na2SO4), filtered and concentrated in vacuo to afford the
product 25 as white crystals (0.09 g; 28%). M.p.: 82–85 °C;
lit. m.p. (Kovár and Jarý 1969): 83–84 °C; Rf = 0.35 (hex-
ane–EtOAc 1:1); FTIR-ATR: νmax: 3404 (ν OH), 2102
N3) cm−1
.
(F) From 1,2:5,6-di-O-isopropylidene-3-O-methanesulfonyl-
α-d-allofuranose (15) the reaction was analogous to the reac-
tion of 14. The reaction mixture was stirred at 120 °C for
180 h. The yield was 87% for 5. Spectral and chromato-
graphic data of the product are in agreement with the data of
the product by (E).
(G) 1,2:5,6-Di-O-isopropylidene-3-O-toluenesulfonyl-α-d-
allofuranose (16) the reaction was analogous to the reaction
of 14. The reaction mixture was stirred at 135 °C for 52 h.
The yield was 74% for 5. Spectral and chromatographic
data of the product are in agreement with the data of the
product by (E).
(ν N3) cm−1
.
1H NMR (CD3OD, 250 MHz) δ = 5.80
(d, J = 3.62 Hz, 1H), 4.66 (d, J = 3.63 Hz, 1H), 4.14 (d,
J = 3.06 Hz, 1H), 3.72 (m, 2H), 3.54 (m, 1H), 3.28 (d,
J = 1.52 Hz, 1H), 1.43 and 1.28 (s, 6H) ppm.
(H): (I) 1,2:5,6-Di-O-isopropylidene-3-O-(N-imidazole-1-
sulfonyl)-α-d-allofuranose (17) (1.4 g; 3.5 mmol) was dis-
solved in toluene (40 ml). Tetra-N-butylammonium bromide
(3.3 g; 0.01 mol; 3 eqv) and NaN3 (0.67 g; 0.01 mol; 3 eqv)
were added to the solution and stirred for 30 min at room
temperature. After the reaction mixture was refluxed for 8 h
between 80 and 90 °C. The reaction was followed by TLC
(EtOAc–hexane 1:1). The precipitated NaBr was filtered.
The organic phase was washed with water (5 × 10 ml),
with saturated NaHCO3 solution (2 × 10 ml) and brine
(1 × 20 ml), dried (MgSO4), filtered and concentrated in
vacuo to afford the product 5 as colourless oil (0.89 g; 90%).
(H): (II) From 17 (30.0 g; 76.9 mmol) the yield was 88%
(21.9 g). Spectral and chromatographic data of the product
are in agreement with the data of the product by (E).
Methyl 3‑deoxy‑l,2‑O‑isopropylidene‑d‑glycero‑
pent‑3‑enofuranuronate (22)
(I) 1,2-O-Isopropylidene-3-O-toluenesulfonyl-α-d-xylofu-
ranuronic acid methyl ester (21) (0.11 g; 0.28 mmol)
was dissolved in DMSO (0.4 ml). Sodium azide (0.07 g;
1.1 mmol; 4 eqv.) in DMSO (2.1 ml) was dropped to the
solution and stirred at 80 °C for 5 h. The reaction mixture
was poured into ice-water (10 ml) and extracted with ethyl
acetate (4 × 3 ml) and the combined organic extracts were
washed with brine (1 × 5 ml), dried (Na2SO4), filtered and
concentrated in vacuo to afford the product 22 as yellow
oil (0.09 g; 90%). Rf = 0.70 (EtOAc–hexane 1:2); FTIR-
ATR: νmax: 1735 (ν C=O); 1627 (ν C=C) cm−1. H NMR
1
(CDCl3, 250 MHz) δ = 6.11 (d, J = 5.35 Hz, 1H), 6.03 (d,
1 3

C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful…
J = 1.93 Hz, 1H), 5.31 (dd, J = 2.34 Hz, J = 4.96 Hz, 1H),
3.78 (s, 3H), 1.39 (s, 6H) ppm.
1H), 4.54 (t, J = 5.44 Hz, 1H), 4.02 (dd, J = 2.71 Hz,
J = 9.01 Hz, 1H), 3.48 (m, 1H), 2.42 (s, 3H), 1.37 (s, 3H),
(II) From 1,2-O-isopropylidene-3-O-toluenesulfonyl-α-d-
ribofuranuronic acid methyl ester (24) (0.10 g; 0.26 mmol)
the reaction was carried out as in the case of method (I).
The product 22 was yellow oil (0.05 g; 92%). Spectral and
chromatographic data of the product are in agreement with
the data of the product by (I).
1.23 (s, 3H) ppm.
1,2‑O‑Isopropylidene‑3‑O‑toluenesulfonyl‑α‑d‑allofura‑
nose (23)
From
1,2:5,6-di-O-isopropylidene-3-O-toluenesulfonyl-
α-d-allofuranose (16) (2.0 g; 4.8 mmol) the reaction was
carried out with the same method as the formation of 19.
After purification of the crude product with column chro-
matography (EtOAc–hexane 2:1) the pure product 23 was
pale yellow oil (1.7 g; 93%). Rf = 0.57 (EtOAc–hexane
2:1); FTIR-ATR: νmax: 3534 (ν OH) cm−1; ESI-MS: 392.3
[M+NH4+]+, calculated: 374.4 m/z. 1H NMR (DMSO-
d6, 250 MHz) δ = 7.83 (d, J = 8.22 Hz, 2H), 7.47 (d,
J = 8.18 Hz, 2H), 5.93 (d, J = 3.68 Hz, 1H), 4.67 (dd,
J = 3.17 Hz, J = 10.09 Hz, 2H), 4.59 (d, J = 6.01 Hz,
1H), 4.52 (t, J = 5.16 Hz, 1H), 4.03 (dd, J = 2.53 Hz,
J = 8.98 Hz, 1H), 3.48 (m, 1H), 2.42 (s, 3H), 1.37 (s, 3H),
1.23 (s, 3H) ppm.
Removal of OH‑5 and OH‑6 isopropylidene protecting
group
1,2‑O‑Isopropylidene‑3‑azido‑3‑deoxy‑α‑d‑allofuranose
(19)
(I) 1,2:5,6-Di-O-isopropylidene-3-azido-3-deoxy-α-d-allofu-
ranose (4) (2.7 g; 9.6 mmol) was dissolved in acetic acid
(44 ml, 75%). The solution was stirred at room temperature
for 2 days and concentrated in vacuo. After evaporation of
the organic solvents, crude product was purified with column
chromatography (EtOAc–hexane 2:1) to afford white crys-
tals (2.2 g; 92%). Spectral and chromatographic data of the
product are in agreement with the data of the product above.
(II) From 4 (14.0 g; 49.1 mmol) the yield was 90% (10.8 g).
Formation of COOH functional group
1,2‑O‑Isopropylidene‑3‑azido‑3‑deoxy‑α‑d‑ribofuranuro‑
nic acid (6)
1,2‑O‑Isopropylidene‑3‑azido‑3‑deoxy‑α‑d‑glucofuranose
(25)
(I) 1,2-O-Isopropylidene-3-azido-3-deoxy-α-d-allofuranose
(19) (0.89 g; 3.7 mmol) was dissolved in MeOH–water 6:4
(10.5 ml) and cooled at 0 °C. Sodium periodate (0.88 g;
4.1 mmol) was dissolved in water (6.3 ml) and added to
the solution of the starting material. The reaction mixture
was stirred for a day at room temperature. The inorganic
salts were precipitated by addition of methanol (15 ml),
were filtered off and washed several times with MeOH.
The solvent was removed and the crude product was
reacted without purification. The aldehyde derivative was
dissolved in acetic acid (18 ml, 50%). Potassium perman-
ganate (0.83 g; 5.2 mmol) was dissolved in water (16 ml)
and added to the solution. The reaction mixture was stirred
for 12 h at room temperature, then was allowed to stand at
0 °C for 2 days. The reaction mixture was filtered, excess
KMnO4 was removed with sodium sulphite. The solution
was adjusted to pH 2–3 with 2 M HCl and extracted with
ethyl acetate (6 × 10 ml). The aqueous phase was satu-
rated with sodium chloride and extracted with ethyl acetate
(1 × 10 ml). The combined organic extracts were extracted
with saturated sodium chloride solution (2 × 15 ml). The
organic phase was dried (MgSO4) and concentrated in
vacuo to afford the crude product. Crystallization of the
crude product from ethyl acetate–n-hexane afforded white
crystals (0.74 g; 88% for 2 steps). M.p.: 110–112 °C; lit.
(I) From 1,2:5,6-di-O-isopropylidene-3-azido-3-deoxy-α-
d-glucofuranose (5) (10.0 g; 35.0 mmol) the reaction was
carried out with the same method as the formation of 19.
After crystallization of the crude product from ethyl ace-
tate–n-hexane 1:1 the pure product 25 was got in the form
of white crystals (5.4 g; 67%). Spectral and chromato-
graphic data of the product are in agreement with the data
of the product above.
(II) From 5 (21.0 g; 73.7 mmol) the yield was 65% (11.7 g).
1,2‑O‑Isopropylidene‑3‑O‑toluenesulfonyl‑α‑d‑glucofura‑
nose (18)
From 1,2:5,6-di-O-isopropylidene-3-O-toluenesulfonyl-α-
d-glucofuranose (10) (6.0 g; 14.5 mmol) the reaction was
carried out with the same method as the formation of 19.
After purification of the crude product with column chro-
matography (EtOAc-hexane 2:1) the pure product 18 was
obtained as colourless oil (5.2 g; 95%); Rf = 0.62 (EtOAc–
hexane 2:1). FTIR-ATR: νmax: 3520 (ν OH) cm−1; ESI-
1
MS: 392.3 [M+NH4]+, calculated: 374.41 m/z. H NMR
(DMSO-d6, 250 MHz) δ = 7.83 (d, J = 8.31 Hz, 2H),
7.47 (d, J = 8.10 Hz, 2H), 5.93 (d, J = 3.83 Hz, 1H), 4.68
(dd, J = 3.32 Hz, J = 7.61 Hz, 2H), 4.62 (d, J = 6.18 Hz,
1 3

A. Nagy et al.
m.p. (Kulinkovich and Timoshchuk 1983): 107–108 °C;
7.48 (d, J = 8.16 Hz, 2H), 6.03 (d, J = 3.68 Hz, 1H), 4.87
(d, J = 3.27 Hz, 1H), 4.79 (d, J = 3.32 Hz, 1H), 4.69 (d,
J = 3.72 Hz, 1H), 2.43 (s, 3H), 1.40 (s, 3H), 1.24 (s, 3H)
ppm.
Rf = 0.44 (chloroform–methanol 3:2). FTIR-ATR: νmax:
3500–2400 (ν COOH), 2107 (ν N3), 1736 (ν C=O) cm−1
;
ESI-MS: 228.2 [M−H]−, calculated: 229.2 m/z; H NMR
(CDCl3, 250 MHz) δ = 7.92 (br s, 1H), 5.87 (d, J = 3.1 Hz,
1H), 4.72 (br m, J = 4.2 Hz, 1H), 4.55 (d, J = 9.5 Hz, 1H),
3.68 (dd, J = 4.2 Hz, J = 9.5 Hz, 1H), 1.53 (s, 3H), 1.32 (s,
3H) ppm.
1
Formation of NH2 from N3‑group
1,2‑O‑Isopropylidene‑3‑amino‑3‑deoxy‑α‑d‑ribofuranuro‑
nic acid (1)
(II) From 19 (10.0 g; 40.8 mmol) the yield was 80% (7.5 g)
for the 2 steps.
1,2-O-Isopropylidene-3-azido-3-deoxy-α-d-ribofuranuronic
acid (6) (0.26 g; 1.1 mmol) was dissolved in methanol
(31.8 ml, c = 35 mmol/l) and reduced with H2 on 10%
Pd/C by H-Cube (parameters: 60 °C, 10 bar, 0.3 ml/min).
After the reaction, the solution was concentrated in vacuo
to give the product 1 as pale yellow oil (0.19 g; 84%).
Rf = 0.51 (chloroform–methanol 3:2). FTIR-ATR: νmax:
3170 (ν NH3+), 2750–2460 and 2170–1900 diffuse (ν
NH3+), 1605 (ν COO−) cm−1. ESI-MS: 204.1 [M+H]+,
calculated: 203.19 m/z. 1H NMR (D2O, 250 MHz) δ = 6.04
(d, J = 3.7 Hz, 1H), 4.97 (t, J = 4.60 Hz, 1H), 4.43 (d,
J = 10.10 Hz, 1H), 3.68 (dd, J = 4.60 Hz, J = 10.10 Hz,
1H), 1.58 (s, 3H), 1.39 (s, 3H) ppm.
1,2‑O‑Isopropylidene‑3‑azido‑3‑deoxy‑α‑d‑
xylofuranuronic acid (7)
(I) From 1,2-O-isopropylidene-3-azido-3-deoxy–α-d-
glucofuranose (25) (5.0 g; 0.02 mol) the reaction was car-
ried out with the same method as the formation of 6. In this
case the reaction mixture was extracted with chloroform
(1×) and dichloromethane (5×). The product 7 was pale
yellow oil (3.8 g; 82% for 2 steps). Rf = 0.11 (hexane–
EtOAc 1:4); FTIR-ATR: νmax: 3462 (ν OH), 2108 (ν N3),
1735 (ν C=O) cm−1; ESI-MS: 228.2 [M−H]−, calculated:
229.2 m/z.
(II) From 25 (10.0 g; 40.8 mmol) the yield was 78% (7.3 g)
for the 2 steps.
1,2‑O‑Isopropylidene‑3‑amino‑3‑deoxy‑α‑d‑xylofuranu‑
ronic acid (2)
1,2‑O‑Isopropylidene‑3‑O‑toluenesulfonyl‑α‑d‑
xylofuranuronic acid (35)
From 1,2-O-isopropylidene-3-azido-3-deoxy-α-d-xylofu-
ranuronic acid (7) (0.20 g; 0.87 mmol) the reaction was car-
ried out with the same method as the formation of 1. The
product was pale yellow oil (0.14 g; 80%). Rf = 0.50 (chlo-
roform–methanol 3:2); FTIR-ATR: νmax: 2977, 2465 (ν
COOH), 1637 (ν COO−), 1560, 1377 (νas COO−, δs CH3)
cm−1; ESI-MS: 204.2 [M+H]+, calculated: 203.19 m/z.
1H NMR (D2O, 250 MHz) δ = 5.97 (d, J = 3.83 Hz, 1H),
4.79 (d, J = 3.85 Hz, 1H), 4.65 (overlapped by the signal
of D2O, 1H), 3.86 (d, J = 3.95 Hz, 1H), 1.39 and 1.21 (s,
6H) ppm.
From
1,2-O-isopropylidene-3-O-toluenesulfonyl-α-d-
glucofuranose (18) (1.0 g; 2.7 mmol) the reaction was carried
out with the same method as the formation of 6. The product
35 was colourless oil (0.26 g; 27% for 2 steps). Rf = 0.70 (to-
luene–EtOAc–EtOH–AcOH 4:2:2:1). FTIR-ATR: νmax
:
3500–2400 (ν COOH), 1756 (ν C=O); ESI-MS: 376.3
[M+NH4]+, calculated: 358.37 m/z; 1H NMR (CDCl3,
250 MHz) δ = 7.75 (d, J = 8.36 Hz, 2H), 7.36 (d,
J = 8.08 Hz, 2H), 6.12 (d, J = 3.42 Hz, 1H), 5.02 (d,
J = 3.35 Hz, 1H), 4.93 (d, J = 3.43 Hz, 1H), 4.82 (d,
J = 3.36 Hz, 1H), 2.45 (s, 3H), 1.49 (s, 3H), 1.34 (s, 3H)
ppm.
Formation of ester derivatives
1,2‑O‑Isopropylidene‑3‑O‑toluenesulfonyl‑α‑d‑xylofuranu‑
ronic acid methyl ester (21)
1,2‑O‑Isopropylidene‑3‑O‑toluenesulfonyl‑α‑d‑ribofuranuro‑
nic acid (36)
1,2-O-Isopropylidene-3-O-toluenesulfonyl-α-d-xylofuranuronic
acid (35) (0.20 g; 0.56 mmol) was dissolved in dichlorometh-
ane (10 ml) and cooled to 0 °C. The cold diazomethane/diethyl
ether solution (15 ml) was dropped to the reaction mixture,
while the yellow colour remained for 20 min. The rest of the
diazomethane was removed with air and the solution was
concentrated in vacuo to get the product 21 as pale yellow oil
(0.20 g; 96%). Rf = 0.66 (EtOAc–hexane 1:1); FTIR-ATR:
From 1,2-O-isopropylidene-3-O-toluenesulfonyl-α-d-allofu
ranose (23) (1.0 g; 2.7 mmol) the reaction was carried
out with the same method as the formation of 6. The pro
duct 36 was pale yellow (0.16 g; 16% for 2 steps).
Rf = 0.73 (toluene–EtOAc–EtOH–AcOH 4:2:2:1). FTIR-
ATR: νmax: 3500–2400 (ν COOH), 1747 (C=O) cm−1; ESI-
1
MS: 376.3 [M+NH4]+, calculated: 358.37 m/z; H NMR
(DMSO-d6, 250 MHz) δ = 7.77 (d, J = 8.25 Hz, 2H),
1 3

C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful…
νmax: 1767 (ν C=O) cm−1. ESI-MS: 390.3 [M+NH4]+, cal-
to give colourless oil (0.32 g; 54%). FTIR-ATR: νmax: 2106
1
1
culated: 372.40 m/z; H NMR (CDCl3, 250 MHz) δ = 7.77
(ν N3), 1738 (ν C=O), 1369 (νas C–CO–O) cm−1. H NMR
(d, J = 8.32 Hz, 2H), 7.37 (d, J = 8.21 Hz, 2H), 6.07
(d, J = 3.50 Hz, 1H), 5.13 (d, J = 3.26 Hz, 1H), 4.84 (d,
J = 3.31 Hz, 1H), 4.77 (d, J = 3.50 Hz, 1H), 3.58 (s, 3H), 2.46
(s, 3H), 1.48 (s, 3H), 1.32 (s, 3H) ppm.
(CDCl3, 250 MHz): δ 5.84 (d, J = 3.49 Hz, 1H), 5.10 (sept,
J = 6.31 Hz, J = 6.33 Hz, J = 6.33 Hz, 1H), 4.67 (m, 1H),
4.45 (d, J = 9.60 Hz, 1H), 3.63 (dd, J = 4.54 Hz, J = 9.56 Hz,
1H), 1.52 and 1.30 (s, 6H), 1.27 and 1.23 (d, 6H) ppm.
1,2‑O‑Isopropylidene‑3‑O‑toluenesulfonyl‑α‑d‑ribofuranu‑
ronic acid methyl ester (24)
Synthesis of uronamide derivatives
N‑Methyl‑1,2‑O‑isopropylidene‑3‑azido‑3‑deoxy‑α‑d‑ribo‑
furanuronamide (31)
From1,2-O-isopropylidene-3-O-toluenesulfonyl-α-d-ribofu
ranuronic acid (36) (0.12 g; 0.33 mmol) the reaction was
carried out with the same method as the formation of
21. The product 24 was pale yellow oil (0.12 g; 96%).
Rf = 0.69 (EtOAc–hexane 1:1); FTIR-ATR: νmax: 1766
(ν C=O) cm−1. ESI-MS: 390.32 [M+NH4]+, calcu-
(I) 1,2-O-Isopropylidene-3-azido-3-deoxy-α-d-ribofuranuronic
acid (6) (0.50 g; 2.2 mmol) was dissolved in dry THF (4.2 ml)
and cooled to 0 °C. Oxalyl chloride (0.34 ml) and dry DMF
(0.16 ml) were dropped to the solution and stirred for 5 h at
room temperature. The solvent was removed, the residue was
dissolved in DCM (1.7 ml) and cooled to 0 °C. Slowly 2 M
MeNH2/THF solution (6.0 ml) was dropped to the solution and
it was stirred for 45 min. The reaction mixture was poured into
ice-water and extracted with DCM (5 × 8 ml). The organic
phase was dried (Na2SO4) and concentrated in vacuo. The
crude product was isolated and purified by column chromatog-
raphy (hexane–EtOAc 1:2) to give white crystals (0.14 g; 27%).
M.p.: 170–173 °C; Rf = 0.34 (EtOAc–hexane 2:1); FTIR-ATR:
νmax: 3368 (ν NH), 2110 (ν N3), 1652 (amide I, ν C=O and ν
C–N), 1538 (amide II) cm−1; ESI-MS: 243.2 [M+H]+, calcu-
lated: 242.2 m/z; 1H NMR (CDCl3, 250 MHz) δ = 6.49 (broad
m, 1H), 5.82 (d, J = 3.4 Hz, 1H), 4.69 (t, J = 4.5 Hz, 1H), 4.45
(d, J = 9.5 Hz, 1H), 3.64 (dd, J = 4.5 Hz, J = 9.5 Hz, 1H),
2.83 (d, J = 5.0 Hz, 3H), 1.54 (s, 3H), 1.34 (s, 3H) ppm.
1
lated: 372.40 m/z; H NMR (CDCl3, 250 MHz) δ = 7.70
(d, J = 8.35 Hz, 2H), 7.30 (d, J = 8.09 Hz, 2H), 6.00
(d, J = 3.53 Hz, 1H), 5.06 (d, J = 3.32 Hz, 1H), 4.77 (d,
J = 3.33 Hz, 1H), 4.71 (d, J = 3.54 Hz, 1H), 3.51 (s, 3H),
2.40 (s, 3H), 1.41 (s, 3H), 1.25 (s, 3H) ppm.
1,2‑O‑Isopropylidene‑3‑azido‑3‑deoxy‑α‑d‑
ribofuranuronic acid methyl ester (37)
From
1,2-O-isopropylidene-3-azido-3-deoxy-α-d-ribofu-
ranuronic acid (6) (0.40 g; 1.7 mmol) the reaction was car-
ried out with the same method as the formation of 21. The
crude product was purified by column chromatography (hex-
ane–EtOAc 1:2). The product (37) was colourless yellow
oil (0.34 g; 80%). Rf = 0.90 (hexane–EtOAc 1:2.5); FTIR-
ATR: νmax: 2115 (ν N3), 1745 (ν C=O) cm−1. ESI-MS:
(II) 1,2-O-Isopropylidene-3-azido-3-deoxy-α-d-ribofuranuronic
acid (6) (0.50 g; 2.2 mmol) was dissolved in dry DMF
(26.4 ml) and cooled to −15 °C. Triethylamine (0.35 ml) and
isobutyl chloroformate (0.32 ml) were dropped to the solu-
tion and stirred. The temperature was kept between −10 and
−15 °C (Solution I). Methylamine in THF (1.12 ml, 2 M)
included TEA (0.35 ml) (Solution II) was cooled to 0 °C and
added to the Solution I after 20 min. The reaction mixture
was stirred for an hour between −10 and −15 °C and even
an hour at 0 °C, then pH was checked (pH 7–8). The pre-
cipitate (TEA.HCl) was filtered, washed with cool DMF. The
solvent was removed, the residue was dissolved in EtOAc
(20 ml) and extracted with cool distilled water (2 × 10 ml),
HCl solution (2 × 10 ml, 2 N), saturated solution of NaHCO3
(2 × 10 ml) and brine (2 × 10 ml). The organic phase was
dried (MgSO4) and concentrated in vacuo. The crude pro
duct was isolated and purified by column chromatography (hex-
ane–EtOAc 1:2) to give white crystals (0.13 g; 25%). Spectral
and chromatographic data of the product are in agreement with
the data of the product by (II).
1
261.2 [M+NH4]+, calculated: 243.2 m/z; H NMR (CDCl3,
250 MHz) δ = 5.86 (d, J = 3.43 Hz, 1H), 4.69 (t, J = 3.97 Hz,
1H), 4.50 (d, J = 9.58 Hz, 1H), 3.79 (s, 3H), 3.64 (dd,
J = 4.50 Hz, J = 9.56 Hz, 1H), 1.52 (s, 3H), 1.31 (s, 3H) ppm.
1,2‑O‑Isopropylidene‑3‑azido‑3‑deoxy‑α‑d‑
ribofuranuronic acid isopropyl ester (38)
1,2-O-Isopropylidene-3-azido-3-deoxy-α-d-ribofuranuronic
acid (6) (0.50 g; 2.2 mmol) was dissolved in CH3CN (4.2 ml)
and cooled at 0 °C. Oxalyl chloride (0.34 ml) and dry DMF
(0.16 ml) were dropped to the solution and stirred for 5 h at
room temperature. The solvent was removed, the residue
was dissolved in CHCl3 (1.7 ml) and cooled to 0 °C. 2-PrOH
(6.0 ml) was dropped slowly to the solution and stirred for
45 min. The reaction mixture was poured onto iced water and
extracted with DCM (5 × 8 ml). The organic phase was dried
(Na2SO4) and concentrated. The crude product was isolated
and purified by column chromatography (hexane–EtOAc 1:2)
1 3

A. Nagy et al.
N‑Methyl‑1,2‑O‑isopropylidene‑3‑azido‑3‑deoxy‑α‑d‑
xylofuranuronamide (30)
70 °C, 10 bar, 0.2 ml/min). The reaction time was 6 h to
give a colourless oil (0.30 g; 95%). Rf = 0.83 (chloro-
form–methanol 3:1); FTIR-ATR: νmax: 3340 (ν NH2 and
NH), 1655 (amide I), 1544 (amide II) cm−1; ESI-MS:
From 7 (0.5 g; 2.2 mmol) the reaction was carried out
with the same method as the formation of 31 with method
(II). The product 30 was pale yellow oil (0.24 g; 46%).
Rf = 0.4 (EtOAc–hexane 1:1); FTIR-ATR: νmax: 3349 (ν
NH), 2106 (ν N3), 1645 (amide I, ν C=O), 1535 (amide II)
1
217.2 [M+H]+, calculated: 216.2 m/z; H NMR (CDCl3,
250 MHz) δ = 6.45 (broad m, 1H), 6.00 (d, J = 3.25 Hz,
1H), 4.81 (dd, J = 3.21 Hz, 2H), 4.54 (d, J = 3.17 Hz, 1H),
2.81 (d, J = 5.02 Hz, 3H), 1.43 (s, 3H), 1.27 (s, 3H) ppm.
cm−1. ESI-MS: 243.2 [M+H]+, calculated: 242.2 m/z; H
1
NMR (CDCl3, 250 MHz) δ = 6.45 (broad m, 1H), 5.87 (d,
J = 3.32 Hz, 1H), 4.70 (d, J = 3.45 Hz, 1H), 4.55 (m, 1H),
4.34 (d, J = 3.43, 1H), 2.83 (d, J = 4.95 Hz, 3H), 1.51 (s,
3H), 1.27 (s, 3H) ppm.
N‑Methyl‑1,2‑O‑isopropylidene‑3‑acetamido‑3‑
deoxy‑α‑d‑ribofuranuronamide (26)
N-Methyl-1,2-O-isopropylidene-3-amino-3-deoxy-α-d-
ribofuranuronamide (28) (0.03 g; 0.14 mmol) was dissolved
in cold mixture of pyridine (0.17 ml) and acetic anhydride
(0.1 ml). The reaction mixture was allowed to stand at 0 °C
for 2 days. The solution was dropped to ice-water (5 ml)
and concentrated in vacuo. The crude product was crys-
tallized from ethyl acetate–petroleum ether to give white
crystals (0.02 g; 56%). M.p.: 208–210 °C; Rf = 0.62 (chlo-
roform–methanol 3:2); FTIR-ATR: νmax: 3391 and 3324
(ν NH), 1655 (amide I), 1546 (amide II) cm−1; ESI-MS:
N‑Methyl‑1,2‑O‑isopropylidene‑3‑amino‑3‑deoxy‑α
‑d‑ribofuranuronamide (28)
(I)
N-Methyl-1,2-O-isopropylidene-3-azido-3-deoxy-α-
d-ribofuranuronamide (31) (0.24 g; 0.99 mmol) was dis-
solved in methanol (28.0 ml, c = 35 mmol/l) and reduced
with H2 on 10% Pd/C by H-Cube (parameters: 60 °C,
10 bar, 0.2 ml/min). After the reaction, the solution was
concentrated in vacuo to give the product 28 as pale yellow
oil (0.18 g; 85%). Rf = 0.86 (chloroform–methanol 3:1);
FTIR-ATR: νmax: 3375 and 3353 (ν NH2 and NH), 1652
(amide I), 1545 (amide II) cm−1; ESI-MS: 217.2 [M+H]+,
calculated: 216.2 m/z; 1H NMR (CDCl3, 250 MHz)
δ = 6.44 (broad m, 1H), 6.00 (d, J = 3.4 Hz, 1H), 4.80
(t, J = 4.4 Hz, 2H), 4.54 (d, J = 9.5 Hz, 1H), 2.81 (d,
J = 5.0 Hz, 3H), 1.43 (s, 3H), 1.27 (s, 3H) ppm.
1
259.2 [M+H]+, calculated: 258.2 m/z; H NMR (CDCl3,
700 MHz) δ = 6.42 (broad m, 1H), 6.08 (d, J = 7.2 Hz,
1H), 5.79 (d, J = 3.4 Hz, 1H), 4.70 (t, J = 4.2 Hz, 1H),
4.23 (ddd, J = 4.2 Hz, J = 10.2 Hz, J = 7.2 Hz, 1H), 4.17
(d, J = 10.2 Hz, 1H), 2.78 (d, J = 5.0 Hz, 3H), 2.00 (s,
3H), 1.48 (s, 3H), 1.28 (s, 3H) ppm.
N‑Methyl‑1,2‑O‑isopropylidene‑3
‑acetamido‑3‑deoxy‑α‑d‑xylofuranuronamide (27)
(II)N-Methyl-1,2-O-isopropylidene-3-azido-3-deoxy-α-d-ri
bofuranuronamide (31) (0.16 g; 0.67 mmol) was dissolved
in dry pyridine (6 ml) and triphenylphosphine (0.34 g;
1.3 mmol) was added to the solution. The reaction mixture
was allowed to stand for 2 h at room temperature. Ammo-
nium hydroxide solution (2.3 ml, 25%) was dropped to the
mixture and it was allowed to stand for 3.5 h. The solution
was filtered and concentrated in vacuo. The residue was
treated with aqueous ammonia (12%) and the solid contain-
ing triphenylphosphine and triphenylphosphine oxide was
removed by filtration. Evaporation of the aqueous solution
gave pale yellow oil as homogeneous product 28 (0.15 g;
92%). Spectral and chromatographic data of the product are
in agreement with the data of the product from the H-Cube
reactor.
From 29 (0.04 g; 0.18 mmol) the reaction was carried out
with the same method as the formation of 26. The pro-
duct 27 was colourless yellow oil (0.015 g; 31%). Rf = 0.70
(chloroform–methanol 3:2); FTIR-ATR: νmax: 3293 (ν NH),
1654 (amide I, ν C=O), 1544 (amide II) cm−1; ESI-MS:
1
259.2 [M+H]+, calculated: 258.2 m/z; H NMR (CDCl3,
250 MHz) δ = 6.83 (m, 1H), 6.61 (m, 1H), 6.04 (m, 1H),
4.73 (m, 2H), 4.41 (m, 1H), 2.78 (d, 3H), 1.90 (s, 3H), 1.43
(s, 3H), 1.25 (s, 3H) ppm.
Synthesis of sugar amino acid dipeptide
3‑Azido‑3‑deoxy‑1,2‑O‑isopropylidene‑α‑d‑ribofuran‑
uronil‑N‑methyl‑1,2‑O‑isopropylidene‑d‑ribofuran‑
uronamide (32)
N‑Methyl‑1,2‑O‑isopropylidene‑
3‑amino‑3‑deoxy‑α‑d‑xylofuranuronamide (29)
1,2-O-Isopropylidene-3-azido-3-deoxy-α-d-ribofuranuronic
acid (6) (0.95 g; 0.42 mmol) was dissolved in dry DMF
(2.5 ml) and cooled at −15 °C. Triethylamine (80 µl) and
isobutyl chloroformate (75 µl) were dropped to the solu-
tion and stirred. The temperature was kept between −10
N-Methyl-1,2-O-isopropylidene-3-azido-3-deoxy-α-d-
xylofuranuronamide (30) (0.31 g; 1.3 mmol) was dissolved
in methanol (37 ml, 35 mmol/l). The starting material was
reduced with H2 on 10% Pd/C by H-Cube (parameters:
1 3

C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful…
and −15 °C for 40 min (Solution I). N-methyl-1,2-O-
isopropylidene-3-amino-3-deoxy-α-d-ribofuranuronamide
(28) (0.09 g; 0.42 mmol) included TEA (80 µl) (Solution II)
was cooled to 0 °C and added to the Solution I. The reaction
mixture was stirred for an hour between −10 and −15 °C and
even an hour at 0 °C, then pH was checked (pH 7–8). The
precipitate (TEA.HCl) was filtered, washed with cool DMF.
The solvent was removed. The crude product was isolated
and purified by column chromatography (hexane–EtOAc
1:1) to give white crystals (0.07 g; 37%). M.p.: 171–174 °C;
Rf = 0.40 (EtOAc); FTIR-ATR: νmax: 3362 and 3229 (ν NH),
2110 (ν N3), 1681 (ν C=O), 1652 (amide I), 1525 (amide
II) cm−1. ESI-MS: 428.3 [M+H]+, calculated: 427.41 m/z.
1H NMR (CDCl3, 250 MHz) δ = 6.86 (broad d, J = 7.9 Hz,
1H), 6.36 (broad m, 1H), 5.83 (d, J = 3.5, 1H), 5.81 (d,
J = 3.5 Hz, 1H), 4.66 (t, J = 4.4 Hz, 1H), 4.64 (t, J = 4.2 Hz,
1H), 4.50 (d, J = 9.5 Hz, 1H), 4.23 (ddd, J = 4.2 Hz,
J = 9.9 Hz, J = 7.2 Hz, 1H), 4.17 (t, J = 9.9 Hz, 1H), 3.63
(dd, J = 4.4 Hz, J = 9.5 Hz, 1H), 2.76 (d, J = 5.0 Hz, 3H),
1.51 (s, 3H), 1.48 (s, 3H), 1.31 (s, 3H), 1.28 (s, 3H) ppm.
The product formed colourless oil (0.13 g; 49%). Rf = 0.52
(ethyl acetate–methanol 4:1); FTIR-ATR: νmax: 3500–2400
(ν COOH), 1719 (broad, ν C=O, ν aromatic, amide I),
1519 (amide II) cm−1; ESI-MS: 426.2 [M+H]+, calcu-
1
lated: 425.19 m/z. H NMR (CDCl3, 250 MHz) δ = 7.55
(m, 3H), 7.30 (overlapped by the signal of CDCl3), 6.08
(d, J = 3.07 Hz, 1H), 4.97 (d, J = 3.27 Hz, 1H), 4.85 (d,
J = 3.26 Hz, 1H), 4.46 (d, J = 3.36 Hz, 1H), 3.82 (m, 1H),
3.44 (m, 1H), 1.45 (s, 3H), 1.28 (s, 3H) ppm.
Acknowledgements The authors gratefully acknowledge Szebasz-
tián Szaniszló for his contribution to the preparative work and Prof.
Imre G Csizmadia for helpful discussion. The authors wish to thank
László Kocsis and Gábor Szirbik from ThalesNano Inc. (Budapest,
Hungary) for their help and advice in hydrogenation reaction and for
their support with the equipment, and Anita Kapros for her help in
MS measurements. This work was supported by Grants from the Hun-
garian Scientific Research Fund (OTKA NK101072).
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Synthesis of N‑protected derivatives
Research involving human participants and/or animals This arti-
cle does not contain any studies with human participants or animals
performed by any of the authors.
1,2‑O‑Isopropylidene‑N‑(9‑fluorenylmethoxy‑carbonyl)‑
3‑amino‑3‑deoxy‑α‑d‑ribofuranuronic acid (33)
The stirred solution of 1,2-O-isopropylidene-3-amino-3-
deoxy-α-d-ribofuranuronic acid (1) (0.20 g; 0.99 mmol)
in methanol–water 2:1 (6.6 ml) is adjusted to pH 8 with
saturated NaHCO3 solution. The solution of Fmoc-OSu
(0.37 g; 1.1 mmol; 1.1 eqv.) in THF (6.8 ml) was added to
this solution and stirred for 48 h at room temperature. Sol-
vents were removed in vacuo. The residue was suspended
in water and extracted with EtOAc (3×). The combined
organic phases were washed with NaHCO3. The aqueous
phase is adjusted to pH 1 with 2 N HCl and extracted with
EtOAc (3×). The organic phase is washed with saturated
NaCl solution, dried (MgSO4) and concentrated in vacuo.
The product formed colourless oil (0.21 g; 51%). Rf = 0.50
(ethyl acetate–methanol 4:1); FTIR-ATR: νmax: 3500-2400
(ν COOH), 3349 (ν NH), 1719 (ν C=O), 1691 (ν aro-
matic), 1600 (amide I), 1523 (amide II) cm−1; ESI-MS:
426.2 [M+H]+, calculated: 425.19 m/z. 1H NMR (DMSO-
d6, 250 MHz) δ = 7.74 (m, 5H), 7.36 (m, 5H), 5.85 (d,
J = 3.29 Hz, 1H), 4.61 (m, 1H), 4.28 (m, 3H), 4.06 (m,
1H), 1.46 (s, 3H), 1.26 (s, 3H) ppm.
References
Altmayer-Henzien A, Declerck V, Farjon J, Merlet D, Guillot R, Ait-
ken DJ (2015) Fine tuning of beta-peptide foldamers: a single
atom replacement holds back the switch from an 8-helix to a
12-helix. Angew Chem Int Ed 54:10807–10810
Austin GN, Baird PD, Fleet GWJ, Peach JM, Smith PW, Watkin
DJ (1987) 3,6-Dideoxy-3,6-imino-1,2-O-isopropylidene-α-d-
glucofuranose as a divergent intermediate for the synthesis of
hydroxylated pyrrolidines: synthesis of 1,4-dideoxy-1,4-imino-
l-gulitol, 1,4-dideoxy-1,4-imino-d-lyxitol, 2S,3S,4R-3,4-di-
hydroxyproline and (lS,2R,8S,RaR)-1,2,8-trihydroxyoctahy-
droindolizine [8-Episwainsonine]. X-ray crystal structure of
(lS,2R,8S,8aR)-1,2,8-trihydroxy-5-oxooctahydroindolizine. Tet-
rahedron 43:3095–3108
Cabrele C, Martinek TA, Reiser O, Berlicki L (2014) Peptides con-
taining β-amino acid patterns: challenges and successes in
medicinal chemistry. J Med Chem 57:9718–9739
Chandrasekhar S, Reddy MS, Jagadeesh B, Prabhakar A, Rao
MHVR, Jagannadh B (2004) Formation of a stable 14-helix in
short oligomers of furanoid cis-β-sugar-amino acid. J Am Chem
Soc 126:13586–13587
Chandrasekhar S, Reddy MS, Babu BN, Jagadeesh B, Prabhakar A,
Jagannadh B (2005) Expanding the conformational pool of cis-
β-sugar amino acid: accommodation of β-hGly motif in robust
14-Helix. J Am Chem Soc 127:9664–9665
Chandrasekhar S, Reddy GPK, Kiran MU, Nagesh C, Jagadeesh B
(2008) Nucleoside derived amino acids (NDA) in foldamer
chemistry: synthesis and conformational studies of homooligom-
ers of modified AZT. Tetrahedron Lett 49:2969–2973
1,2‑O‑Isopropylidene‑N‑(9‑fluorenylmethoxy‑carbonyl)‑
3‑amino‑3‑deoxy‑α‑d‑xylofuranuronic acid (34)
From 1,2-O-isopropylidene-3-amino-3-deoxy-α-d-xylofura
nuronic acid (2) (0.13 g; 0.64 mmol) the reaction was car-
ried out with the same method as the formation of (33).
Chandrasekhar S, Kiranmai N, Kiran MU, Devi AS, Reddy
GPK, Idrisc M, Jagadeesh B (2010) Novel helical foldam-
ers: organized heterogeneous backbone folding in 1:1 α/
1 3

A. Nagy et al.
Intramolecular amide stacking and its competition with hydrogen
bonding in a small foldamer. J Am Chem Soc 131:14243–14245
Kiss L, Fülöp F (2014) Synthesis of carbocyclic and heterocyclic
β-aminocarboxylic acids. Chem Rev 114:1116–1169
nucleoside-derived-β-amino acid sequences. Chem Commun
46:6962–6964
Cheng RP, Gellman SH, DeGrado WF (2001) α-Peptides: from struc-
ture to function. Chem Rev 101:3219–3232
Knapp K, Górecki M, Frelek J, Luboradzki R, Hollósi M, Zs Majer,
Vass E (2014) Comprehensive chiroptical study of proline-con-
taining diamide compounds. Chirality 26:228–242
Kovárˇ J, Jarý J (1969) Amino sugars. XXI. Synthesis of 3,6-diamino-
3,6-dideoxy-d-glucose and its derivatives. Collect Czech Chem
Commun 34:2619–2626
Kulinkovich LN, Timoshchuk VA (1983) Synthesis of unsaturated
nucleosides of uronic acids. Zh Obshch Khim 53:1652–1655
Mándity IM, Fülöp F (2015) An overview of peptide and peptoid
foldamers in medicinal chemistry. Expert Opin Drug Discov
10(11):1163–1177
Martinek TA, Fülöp F (2012) Peptidic foldamers: ramping up diver-
sity. Chem Soc Rev 41:687–702
Nayak UG, Whistler RL (1969) Nucleophilic displacement in
1,2:5,6-di-O-isopropylidene-3-O-(p-tolylsulfonyl)-α-d-
glucofuranose. J Org Chem 34:3819–3822
Pandey SK, Jogdand GF, Oliveira JCA, Mata RA, Rajamohanan PR,
Ramana CV (2011) Synthesis and structural characterization of
homochiral homo-oligomers of parent cis- and trans-Furanoid-β-
amino acids. Chem Eur J 17:12946–12954
Perczel A, Hollósi M, Foxman BM, Fasman GD (1991) Conforma-
tional analysis of pseudocyclic hexapeptides based on quantitative
circular dichroism (CD), NOE, and X-ray data. The pure CD spec-
tra of type I and type II β-turns. J Am Chem Soc 113:9772–9784
Pilsl LKA, Reiser O (2011) α/β-Peptide foldamers: state of the art.
Amino Acids 41:709–718
Pohl G, Gorrea E, Branchadell V, Ortuño RM, Perczel A, Gy Tarczay
(2013) Foldamers of β-peptides: conformational preference of
peptides formed by rigid building blocks The first MI-IR spectra
of a triamide nanosystem. Amino Acids 45(4):957–973
Reckendorf Z, Meyer W (1968) Diaminozucker, IX. Synthese der
3-Amino-3-desoxy- und 3.6-Diamino-3.6-didesoxy-d-glucose.
Chem Ber 101:3802–3807
Rjabovs V, Turks M (2013) Tetrahydrofuran amino acids of the past
decade. Tetrahedron 69:10693–10710
Schmidt OTH (1963) Reaction of carbohydrates. In: Whistler RL,
Wolfrom ML, BeMiller JN (eds) Methods Carbohydr Chem, vol
2. Academic Press, New York, pp 318–325
Csordás B, Nagy A, Harmat V, Zsoldos-Mády V, Leveles I, Pin-
tér I, Farkas V, Perczel A (2016) Origin of problems related to
Staudinger reduction in carbopeptoide syntheses. Amino Acids.
doi:10.100/s00726-016-2289-x
Declerck V, Aitken DJ (2011) A refined synthesis of enantiomeri-
cally pure 2-aminocyclobutane carboxylic acids. Amino Acids
41:587–595
Ferreira SB, Sodero ACR, Cardoso MFC, Lima ES, Kaiser CR,
Silva FP FP Jr, Ferreira VF (2010) Synthesis, biological activ-
ity, and molecular modeling studies of 1H-1,2,3-triazole deriva-
tives of carbohydrates as α-glucosidases inhibitors. J Med Chem
53:2364–2375
Giri AG, Jogdand GF, Rajamohanan PR, Pandey SK, Ramana CV
(2012) Synthesis and structural characterization of homochiral
homo-oligomers of cis-γ-methoxy-substituted cis- and trans-
Furanoid-β-Amino acids. Eur J Org Chem 13:2656–2663
Giuliano MW, Maynard SJ, Almeida AM, Reidenbach AG, Guo
L, Ulrich EC, Guzei IA, Gellman SH (2013) Evaluation of a
cyclopentane-based γ-amino acid for the ability to promote α/γ-
peptide secondary structure. J Org Chem 78:12351–12361
Gomtsyan A, Savelyeva I, Belyakov S, Kalvinsh I (1992) Synthe-
sis of methyl 3-amino-deoxy-d-alluronate. Carbohydr Res
232:341–348
Gorrea E, Pohl G, Nolis P, Celis S, Burusco KK, Branchadell V, Per-
czel A, Ortuño RM (2012) Secondary structure of short beta-
peptides as the chiral expression of monomeric building units:
a rational and predictive model. J Org Chem 77(21):9795–9806
Gruner SAW, Gy Kéri, Venetainer A, Kessler H (2001) Sugar amino
acid containing somatostatin analogues that induce apoptosis in
both drug-sensitive and multidrug-resistant tumor cells. Org Lett
3:3723–3725
Gruner SAW, Locardi E, Lohof E, Kessler H (2002a) Carbohydrate-
based mimetics in drug design: sugar amino acids and carbohy-
drate scaffolds. Chem Rev 102:491–514
Gruner SAW, Truffault V, Voll G, Locardi E, Stöckle M, Kessler H
(2002b) Design, synthesis, and NMR structure of linear and
cyclic oligomers containing novel furanoid sugar amino acids.
Chem Eur J 8:4365–4376
Guichard G, Huc I (2011) Synthetic foldamers. Chem Commun
47:5933–5941
Hale KJ, Hough L, Manaviazar S, Calabrese A (2015) Rules and
stereoelectronic guidelines for the anionic nucleophilic dis-
placement of furanoside and furanose O-sulfonates. Org Lett
17:1738–1741
Hall LD, Miller DC (1976) Fluorinated sulphonic esters of sug-
ars: their synthesis and reactions with pyridine. Carbohydr Res
47:299–305
Helferich B, Dressler H, Griebel R (1939) Ester der Methansulfon-
säure in der Zuckergruppe. J Prakt Chem 153:285–299
Hetényi A, Tóth GK, Cs Somlai, Vass E, Martinek TA, Fülöp F
(2009) Stabilisation of peptide foldamers in an aqueous medium
by incorporation of azapeptide building blocks. Chem Eur J
15:10736–10741
Theoneste M, Stephane G, Veronique C (2009) Synthesis and anti-
bacterial activity of aminodeoxyglucose derivatives against Lis‑
teria innocua and Salmonella typhimurium. J Agric Food Chem
57:8770–8775
Threlfall R, Davies A, Howarth NM, Fisher J, Cosstick R (2008) Pep-
tides derived from nucleoside β-amino acids form an unusual
8-helix. Chem Commun 5:585–587
Vatéle JM, Hanessian S (1996) Design and reactivity of organic
functional groups—preparation and nucleophilic displacement
reactions of imidazole-l-sulfonates (imidazylates). Tetrahedron
52:10557–10568
Watterson PM, Pickering L, Smith MD, Hudson SJ, Marsh PR,
Mordaunt JE, Watkin DJ, Newman CJ, Fleet GWJ (1999) 3-Azi-
dotetrahydrofuran-2-Carboxylates: a family of five-ring templated
β-aminoacid foldamers? Tetrahedron Asymmetry 10:1855–1859
Whistler RL, Doner LW (1972) General carbohydrate methods. In:
Whistler RL, BeMiller JN (eds) Methods Carbohydr Chem, vol
6. Academic Press, New York, pp 215–217
Horne WS, Gellman SH (2008) Foldamers with heterogeneous back-
bones. Acc Chem Res 41:1399–1408
Jagannadh B, Reddy MS, Rao CL, Prabhakar A, Jagadeesh B, Chan-
drasekhar S (2006) Self-assembly of cyclic homo- and hetero-β-
peptides with cis-furanoid sugar amino acid and β-hGly as build-
ing blocks. Chem Commun 46:4847–4849
Zsoldos-Mády V, Zbiral E (1986) A new approach to 6-Deoxy-
d-allofuranose- and 6-Deoxy-l-talofuranose derivatives from
1,2:5,6-Di-O-isopropylidene-α-d-glucofuranose. Monatsh Chem
117:1325–1338
James WH III, Müller CW, Buchanan EG, Nix MGD, Guo L, Roskop
L, Gordon MS, Slipchenko LV, Gellman SH, Zwier TS (2009)
1 3