Synthesis of cyclically constrained sugar derived α/β- and α/γ-peptides

Article abstract of DOI:10.1039/c2ob26992a

A general approach to enantiopure conformationally constrained sugar derived α/β- and α/γ-peptides has been established. Five-membered ring α/β-peptides were synthesized via formyl C-glycofuranosides, easy available from hexose-derived azido-2-equatorial-OH- glycopyranosides by DAST-promoted ring contraction. By means of a regioselective oxidation with TEMPO at C-6 of hexose-derived 3-azido glycopyranosides as the key step, two- and three-residue α/γ-peptides having a six-membered ring were obtained in good yields and under very simple experimental conditions.

Full text of DOI:10.1039/c2ob26992a

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TABLE OF CONTENTS
5
Synthesis of cyclically constrained sugar derived
α/β- and α/γ-peptides
Gly
HN
Ph
O
O
O
γ
β
D-Glucose
Antonio Franconetti, Sorel Jatunov, Pastora Borrachero, Manuel
Gómez-Guillén, and Francisca Cabrera-Escribano*
OR
α
HO
OMe
O
N3
O
C6
Gly
10 An economic, diversity-oriented strategy to access novel
enantiopure, both five- and six-membered ring α/β- and α/γ-
hybrid peptides containing sugar amino acids residues has been
developed.
N3
β
α
Gly
RO
C1
O
O
15
20
25
30
35
40
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PAPER
Synthesis of cyclically constrained sugar derived /- and /-peptides
Antonio Franconetti,a Sorel Jatunov,a Pastora Borrachero,a Manuel Gómez-Guilléna and Francisca
Cabrera-Escribano*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A general approach to enantiopure conformationally constrained sugar derived /- and /-peptides has
been established. Five-membered ring /-peptides were synthesized via formyl C-glycofuranosides,
easy available from hexose-derived azido-2-equatorial-OH-glycopyranosides by DAST-promoted ring
contraction. By means of a regioselective oxidation with TEMPO at C-6 of hexose-derived 3-azido
10 glycopyranosides as the key step, two- and three residue /-peptides having a six-membered ring were
obtained in good yields and under very simple experimental conditions.
45 improved efficacy for inhibiting HIV infection relative to /-
Introduction
peptides that lack cyclic -residues.6 On the other hand, it has
been shown that appropriately designed sequences, with a high
proportion of the cyclically constrained residues derived from
trans-2-amino-cyclohexanecarboxylic acid (ACHC), can self-
50 assemble to form lyotropic liquid crystalline (LC) phases in
aqueous solution.7 Self-assembly of ACHC-rich β-peptides leads
to nanofibers that serve as the LC mesogens. A description of
factors governing self-assembly of ACHC-rich β-peptides into
nanostructures that form LC phases as well as the use of this
55 information to design nanostructures that are functionalized with
biological recognition groups have been also provided.8
Additional examples in the literature have shown nanofibers and
lyotropic LCs to be useful for nanocrystal templation,9 biological
sensing,10 NMR RDC analysis,11 and as NMR alignment media
60 for small organic molecules in aqueous solution to provide
enantiodiscrimination.12
The biological function of proteins and RNA, including catalysis
and recognition, depends not only on the specificity of
15 macromolecular interactions but also on the folding pattern of
these macromolecules that leads to well organized structures.1
Since many proteins exert their biological activity through
relatively small regions of their folded surface, their activity
could be reproduced by smaller molecules designed in a way that
20 they not only conserve the function of the protein but also have
better pharmacokinetic and pharmacodynamic properties.
Unnatural oligomers that can reproduce the three-dimensional
shapes and side-chain projection patterns characteristic of natural
polypeptides offer a basis for rational development of protein-
25 protein interaction antagonists.2
It has been shown, in contrast to -amino acids which are
components of proteins, that short β-, -, and -amino acid
oligomers, especially those that have conformational restrictions,
adopt well defined tridimensional structures. The study of non-
30 natural oligomers with discrete folding propensities, so called

-Amino acid residues can be endowed with higher intrinsic
folding propensities than those of  residues by use of cyclic
constraints to limit backbone torsional mobility, and this capacity
65 for residue-based rigidification has proven to be important for
both the structure of - and /-peptide foldamers.6,13 Analogous
benefits should result from the use of constrained γ-amino acid
residues, but it is difficult to explore this hypothesis because only
a few types of ring-containing γ-amino acids are known.14
70 Furthermore, these compounds represent analogues of γ-
aminobutyric acid (GABA) which are known to exhibit a wide
range of biological properties15 and have found diverse industrial
applications.16 Various GABA derivatives, including -amino
esters, have been recently prepared17 via an ene-imine reductive
75 coupling reaction catalyzed by a nickel-1,10-phenanthroline
complex. γ-Amino acids containing a cyclohexyl constraint on
the C-Cγ bond and a variable side chain at Chave been
foldamers,3 has demonstrated that
a variety of synthetic
backbones can show biopolymer-like conformational behavior.
To gain deeper understanding of folding and the functions of the
folded molecules, many artificial foldamers have been
35 developed.4 Early work in this area focused on oligomers
comprised of a single type of monomer subunits, but recent
efforts have highlighted the potential of mixed or
“heterogeneous” backbones to expand the structural and
functional repertoire of foldamers.5 Gellman and co-workers have
40 developed α/β-peptide analogues of HIV gp41 that show potent
antiviral activity coupled with improved stability to degradation
by proteases. Indeed, they have shown that cyclic replacements
can substantially improve the affinity of gp41-mimetic /-
peptides for a complementary protein surface, which leads to
This journal is © The Royal Society of Chemistry 2012
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synthesized18 by a pyrrolidine-catalyzed Michael addition of an
Scheme 1 shows our synthetic carbohydrate-based strategy that
aldehyde to 1-nitrocyclohexene as a key step, and it has been
demonstrated that this new type of γ-amino acid residue supports
holds several interesting features: (a) it is chemically efficient,
starting from readily available sugar derivatives (e.g., 8);24 (b)
helix formation by an /γ-peptide backbone. In addition, access 45 amino acids containing both
a cyclopentyl or cyclohexyl
5
to cyclic γ-amino acids with up to three stereocenters has been
described by enantioselective intramolecular Michael addition of
nitronates onto conjugated esters.19 However, neither the
synthesis of enantiomerically pure γ-amino acids nor the
constraint on the C-C bond and C-C-C segment,
respectively, are affordable; (c) importantly, with this
carbohydrate-based procedure, up to four or five contiguous
stereocenters can be assembled, which is
a remarkable
synthesis of cyclically constrained variants has been widely 50 improvement in comparison with related systems 6 and 7,
10 reported.20
One of the first stages in the generation of non natural oligo-
previously described;18,19 (d) in addition to the diversity supplied
by introducing different available -amino acids, sugar
stereodiversity can be also exploited.
and polymeric novel structures is the identification of monomer
units with predictable stereochemical and conformational
preferences. Carbohydrates bearing both an amino and carboxylic
15 acid functionality have been extensively investigated21 and have
found wide applications in the construction of diverse novel
structures with unique properties.20,22 In this context, since
carbohydrates are conformationally restricted structures with the
added hydrogen bond capability and enantiopure diversity we
20 envisaged an easy and advantageous approach to a new kind of
cyclic /- and /-hybrid peptides (Figure 1) as potential
monomer structure building blocks for foldamers, and self-
assembling nanostructured LC phases. In addition, the
carbohydrate-based hybrid backbones described herein can be
25 considered as a novel category of sugar amino acids.21f
Results and Discussion
55
Here we report a new synthetic approach towards enantiopure C-
glycofuranoside-based /-peptides of structures 1 and 2, and the
preparation of a variety of six membered ring / sugar-peptide
30 hybrids, 3-5, in a straightforward way from D-glucose.
Scheme 1 Main features of the synthetic strategy.
The synthesis of /-glycopeptides of general structures 1 and
2 can be achieved via formyl C-glycofuranosides.25 The key step
in this hydrolysis strategy is clearly
a DAST-mediated
60 rearrangement reaction which involves ring contraction of
hexose-derived equatorial-2-OH-glycopyranosides, leading to
formyl C-glycofuranosides under remarkably mild conditions.
Thus, the precursors 13 and 15 of compounds having general
structures 1 and 2 have been successfully obtained from the
65 known
methyl
3-azido-4,6-O-benzylidene-3-deoxy--D-
allopyranoside (8).24
Treatment of compound 8 with diethylaminosulfur trifluoride
(DAST) in refluxing acetonitrile for 12 min as described
previously26 gave the 2,5-anhydro-1-fluoro-1-O-methyl-D-altritol
70 9 (73%) as an epimeric mixture which contains a masked formyl
function (Scheme 2).
Fig. 1 Structure of the new cyclically constrained /- and /-sugar-
peptide hybrids.
Conformational stability and specificity are provided by the
35 preorganized - or -amino acid residues, while diversity can be
supplied by readily available -amino acids. Compounds of types
1 an 2 are structural and configurationally related to the natural
antifungal antibiotic Cispentacin,23 (Figure 2) which have been
used as a peptidomimetic for proline.
40
Fig. 2 Cyclically constrained - and -amino acids.
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9.63 ppm, as well as the two acetyl proton singlets at  2.17 and
2.11 ppm, and in its 13C NMR spectrum, three carbonyl carbon
40 signals ( 199.2 ppm for the aldehydic one; 170.6 and 170.3 ppm
for the two ester carbonyl carbons). In turn, primary alcohol 18
had a NMR spectra showing a broad OH-proton signal at  ~1.95
ppm and signals for the two C(1) protons (doublet at  3.82 ppm)
and for the C(1) nucleus ( 62.0 ppm). Oxidation of 18 with
45 aqueous dichromate/sulfuric acid (Jones‘ reagent, 30 ºC, r. t., 1
h) gave the 4,6-di-O-acetyl--azido acid 12 in 72%.
Ph
Ph
O
O
N3
O
DAST, MeCN
O
OMe
H
O
reflux, 12 min, 73 %
[ref. 26]
HO
N3
OMe
O
9
F
8
MeOH, PTSA
r.t., 1h
Na(CN)BH3, THF, HCl/Et2O
r.t., 20 min
64%
93%
RO
N3
HO
R
OMe
OMe
RO
BnO
O
O
OMe
10 R= H
11 R= OAc
14 R= N3
1) Ph3P, THF, r.t., 8 h
2) H2O, 20 h, 95%
Ac2O, pyridine, 0 ºC
94%
15 R= NH2
1) Ph3P, THF, r.t., 8 h
2) EDCI, HOBt, DIPEA,
Boc-Gly-OH, CH2Cl2, r.t., 20 h
1) TFA-H2O 9:1, r.t., 1 h
2) Jones' reagent -30 ºC to r.t., 1 h
65%
82%
1) TFA-H2O 9:1
NaBH(OAc)3,
r.t., 1 h
AcO
N3
O
Jones' reagent
30 ºC, r.t., 1 h
imidazole,
AcO
N3
2) Ac2O, pyridine
0 ºC
AcO
N3
H
N
DCE, r.t., 20 h
OH
HO
AcO
9
12
N
O
OH
H
O
92%
70%
from 9
72%
H
AcO
AcO
O
O
O
O
BnO
12
O
O
EDCI, HOBt, DIPEA,
HCl EtO-Gly-NH2, CH2Cl2, r.t., 18 h
OMe
67%
17
18
16
N3
AcO
O
H
N
AcO
OEt
O
O
Scheme 3 Alternative synthesis of the -azido acid 12.
13
50
To obtain the methoxymethyl glycofuranosyl glycine
derivative 16, being a precursor of the structure 2, and the
previous vicinal amino alcohol 15 we started from 9 (Scheme 2).
Thus, reduction of 9 dissolved in dry THF, with sodium
cyanoborohydride (12.7 mol equiv) in the presence of 3Å
Scheme 2 Synthesis of /-glycopeptides.
Compound 9 was transformed, by the action of PTSA and
methanol, into the 4,6-O-deprotected dimethyl acetal 10 in high
yield (93%). When the preceding reaction was performed without
purifying the product, and this crude product was subjected to
standard acetylation conditions, the 4,6-di-O-acetyl derivative 11
(94% after column chromatography) was obtained.26 Hydrolysis
5
55 molecular sieves (r. t., 15 min, and then HCl/Et2O, 5 min)
afforded compound 14 in 64% yield, which was subjected to the
Staudinger reaction to give the amine 15 (95%). On its turn,
Staudinger reaction of 14, by using Boc-Gly-OH gave the
1
dipeptidomimetic 16 in high yield (82%). For this compound H
10 of 11 with 9:1 trifluoroacetic acid (TFA)/H2O, followed by
oxidation with aqueous sodium dichromate/sulfuric acid (Jones'
reagent), gave the 4,6-di-O-acetyl--azido acid 12 in 65% yield.
Transformation of 12 into 13 was easily achieved for protected
glycine (EDCI, HOBt, DIPEA, HClEtO-Gly-NH2, CH2Cl2, r. t.,
15 18 h) in good yield (67%). Compound 12 showed in the 13C
NMR spectrum three carbonyl carbon signals, among them that
of the highest  value (172.0 ppm) being assigned to the carboxyl
carbon. The 1H NMR spectrum of compound 13 (Table 1)
showed a triplet (J 5.0 Hz) at  7.07 ppm assigned to the NH
20 proton, and two signals for the two glycine diastereotopic protons
at  4.11 and 4.07 ppm, as well as the typical quartet/triplet signal
tandem for the O-ethyl protons of an ester at  4.23 and 1.29
ppm; corresponding signals in the 13C NMR spectrum (Table 2)
and the high-resolution mass spectrum corroborated the proposed
25 structure.
60 NMR coupling constants contrast sharply with those expected for
a furanose ring, suggesting a conformational deviation. Thus, the
J2,3 value of 8 Hz observed matched with a dihedral angle H2-C2-
C3-H3 next to 0º, and the J4,5 of 3 Hz is remarkably lower than
the corresponding usual value (7.5-8.5 Hz) observed for a
65 furanose ring.25 Preliminary molecular mechanics calculations26,
27 showed a sole low-energy conformer (below 10 kJ/mol) with a
dihedral angle (17-23º) in agreement with the NMR data
indicated above. On the other hand, it is noteworthy that
introduction of a peptide chain at C-3 provokes a shielding of this
70 nucleus in comparison with its  value in compounds 14 or 15
(Table 2); in relation to  values of H-3, a deshielding of 0.4 ppm
can be observed from 14 or 15 to 16 (Table 1), both features are
consistent with a -gauche effect.
The synthesis of /-glycopeptides of types 3-5, was carried
75 out starting from 8 and from its derivative, the known methyl 3-
azido-2-O-benzoyl-4,6-O-benzylidene-3-deoxy--D-allopyrano-
side (23),24 as shown in Schemes 4 and 5, respectively.
An alternative, higher yielding experimental protocol, in which
the formyl C-glycofuranoside synthetic equivalent 9 is subjected
to in situ hydrolysis, acetylation, and reduction can be applied to
obtain azido acid 12. Adopting this one-pot procedure (Scheme
30 3), crude diacetylated aldehyde 17, obtained in situ by hydrolysis
(9:1 TFA/H2O, r.t., 1 h) and subsequent acetylation (Ac2O,
pyridine, 0 ºC), reacted with sodium triacetoxyborohydride (1.4
mol equiv) and imidazole (1.4 mol equiv) in dry 1,2-
dichoroethane for 20 h, furnishing primary alcohol 18 (56% after
35 column chromatography). A sample of the crude aldehyde 17 was
1
purified by column chromatography and showed in its H NMR
spectrum the formyl proton signal as a doublet (J 1.5 Hz) at 

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C, MeOH, 12 min) gave compound 27, a /-glycopeptide of
1
type 3 in quantitative yield. The H NMR spectrum (Table 1) of
N3
O
N3
O
TCCA/TEMPO/NaBr
acetone, aq NaHCO3,
r.t., 1 h
AcOH-H2O 7:3
reflux, 30 min
compound 26 showed a triplet (J 5.0 Hz) at  7.17 ppm for the
50 amide proton, a signal at 4.10 ppm (dd, J 5.5 and 9.5 Hz) for two
methylenic protons of the glycine residue, a singlet for the
anomeric methyl group at 3.48 ppm, as well as the typical
quartet/triplet signal tandem for the O-ethyl protons of an ester;
corresponding signals in the 13C NMR spectrum (Table 2) and the
55 high-resolution mass spectrum corroborated the proposed
structure. Crude 3-amino derivative 27 was chromatographically
homogeneous and was used for further transformation without
purification by column chromatography.
RO
O
OR
HO
OH
8
quant.
[ref.24]
HO
HO
OMe
OMe
19
EDCI, HOBt, DIPEA,
HCl EtO-Gly-NH2,
CH2Cl2, r.t., 18 h
20 R= H
Ac2O, pyridine, 0 ºC
87% from 19
21 R= OAc
67%
N3
AcO
OAc
O
H
N
EtO
O
OMe
O
22
Scheme 4 Synthesis of the /-amino acid precursor 22 having general
structure 3.
N3
7:3 AcOH/H2O,
reflux, 30 min
Ph
O
HO
OBz
O
O
98%
HO
BzO
5
Hydrolysis of 8 (Scheme 4) by treatment with AcOH/H2O
(7:3, reflux, 30 min) gave quantitatively the triol 19.24 Selective
oxidation of the primary alcohol at C-6 of 19 was carried out by
treatment with the 2,2,6,6-tetramethylpiperidine-N-oxyl radical
(TEMPO)/NaBr/trichloro-isocyanuric acid (TCCA) in acetone,
N3
OMe
O
OMe
TCCA/TEMPO/NaBr,
acetone, aq NaHCO3,
r.t., 45 min
24
23
77%
N3
O
N3
HO
O
OBz
2M TMSCHN2 in hexane,
MeOH/MeCN, r.t., 4 h
HO
O
OBz
MeO
HO
10 and subsequent in situ acetylation of the crude diol 20, gave the
desired alluronic acid 21 in high yield (87%). Compound 21
84%
OMe
O
OMe
28
quant.
25
82%
1
showed in its H NMR spectrum the singlet at 3.50 ppm for the
EDCI, HOBt, DIPEA,
HCl EtO-Gly-NH2,
CH2Cl2, r.t., 18 h
H2, Pd-C, MeOH, 2 h
anomeric methyl group protons as well as the two acetyl proton
singlets at  2.14 and 2.17 ppm, and in its 13C NMR spectrum
15 three carbonyl carbon signals, among them that of the highest 
value (171.3 ppm) being assigned to the carboxyl carbon.
Transformation of 21 into 22 was easily achieved for protected
glycine (EDCI, HOBt, DIPEA, HCl∙EtO-Gly-NH2, CH2Cl2, r.t.,
18 h) in good yield (67%). Compound 22, which is a precursor of
NH2
N3
HO
MeO
O
OBz
HO
OBz
O
H
N
O
OMe
EtO
O
OMe
O
29
26
quant.
H2, Pd-C, MeOH,
12 min
EDCI, HOBt, DIPEA,
Boc-Gly-OH, CH2Cl2,
r.t., 18 h
46%
O
1
H
N
NH2
20 structure 3, shows in its H NMR spectrum (Table 1) a triplet (J
O
HN
HO
OBz
4.5 Hz) at  6.90 ppm for the amide proton, two signals at 4.07
and 3.94 ppm (dd each for 1H, J 5.4 and 18.3 Hz) for two
methylenic proton of glycine residue, a singlet for the anomeric
methyl group at 3.44 ppm, as well as the typical quartet/triplet
25 signal tandem (4.21 and 1.26 ppm) for the O-ethyl protons of an
ester; corresponding signals in the 13C NMR spectrum (Table 2)
and the high-resolution mass spectrum corroborated the /-
dipeptidomimetic proposed structure.
Scheme 5 shows the synthesis of the /-glycopeptides 26, 27,
30 30, and 31, owning general structures 3-5. To obtain the key
compound, the alluronic acid derivative 25, methyl -D-
allopyranoside 23 was first hydrolyzed, by the action of
AcOH/H2O (7:3, reflux, 30 min, 98%), to the 4,6-O-deprotected
derivative 24, the structure of which was deduced from its high-
35 resolution mass spectrum and the absence of any benzylic proton
O
H
HO
O
OBz
O
N
EtO
O
OMe
MeO
O
OMe
O
27
30
56%
EDCI, HOBt, DIPEA,
Boc-Gly-OH, CH2Cl2,
r.t., 18 h
O
H
N
O
HN
O
HO
O
OBz
O
O
H
N
EtO
OMe
31
60
Scheme 5 Synthesis of /-glycopeptides.
Alternatively, compound 25 was transformed into the methyl
uronate 28, by treatment with a solution of 2M TMSCHN2
(trimethylsilyl-diazomethane) in hexane (MeOH/MeCN, r.t., 4 h),
65 in good yield (84%); its spectral data (mainly MS and NMR)
corroborated this structure: the novel methyl ester function gave
rise to a singlet at 3.86 ppm for the three methyl protons, as
well as an ester carbonyl signal at 170.8 ppm and an additional
methyl carbon signal at 53.0 ppm. Reduction of the azido
1
nor carbon atom in its H and 13C NMR spectra, in particular the
easily observable singlet at  5.62 ppm for the benzylic proton for
compound 23. Selective oxidation of the primary alcohol at C-6
of 24 was accomplished with TEMPO/NaBr/TCCA in acetone to
40 give the desired carboxylic acid 25 in 77% yield. Compound 25
showed in its 13C NMR spectrum two carbonyl carbon signals,
among them that of the highest  value (171.2 ppm) being
assigned to the carboxyl carbon. Transformation of 25 into the
azido /- glycopeptide 26 was easily achieved using protected
45 glycine (EDCI, HOBt, DIPEA, HCl∙EtO-Gly-NH2, CH2Cl2, r.t.,
18 h) in good yield (82%). Catalytic hydrogenation of 26 (H2, Pd-
70 function in 28 by using H2, Pd-C (MeOH,
2 h) gave
quantitatively the amino ester 29. Coupling of this compound
with protected glycine as a -amino acid, (EDCI, HOBt, DIPEA,
Boc-Gly-OH, CH2Cl2, r.t., 18 h) furnished the /-sugar peptide
Org. Biomol. Chem., 2012, [vol], 00–00

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1
hybrid 30 (46%) showing a structure of type 4. The H NMR 25 signal 7.26-7.22 ppm) being assigned to the ethyl glycinate
spectrum (Table 1) of compound 30 showed as the most relevant
signals, a doublet (J 6.5 Hz) at 7.70 ppm for the NH amide proton
at C-3 and a singlet for the anomeric methyl group at 3.51 ppm,
Boc-glycine residue being evidenced by a triplet (J 6 Hz) at 
residue, and a triplet (J 6.0 Hz) at 5.49 ppm for the C(3) NH
proton; the ethoxycarbonyl glycine residue at position 6 gave also
a signal (dd, J 6.0 and J 14.5 Hz) at 4.09 ppm for the two
methylenic protons, and the typical quartet/triplet signal tandem
5
5.30 ppm for the amide proton, two signals at 3.96 ppm (dd, J 5.0 30 (4.22 and 1.28 ppm) for the O-ethyl protons of an ester; a singlet
and 15.0 Hz) and 3.74 ppm (dd, J 5.0 and 16.0 Hz) for the two
methylenic protons, and a singlet at 1.43 ppm for nine protons
assigned to the t-butyl group; corresponding signals in the 13C
10 NMR spectrum (Table 2) and the high-resolution mass spectrum
corroborated the proposed structure.
for the anomeric methyl group at 3.49 ppm and a singlet at 1.41
ppm for nine protons assigned to the t-butyl group were also
observed in the spectrum. It is noteworthy that as it was observed
for compound 30, two signals at 4.00 and 3.79 ppm appear for
35 each of the diasterotopic methylenic protons of the Boc-glycine
residue; corresponding signals in the 13C NMR spectrum (Table
2) and the high-resolution mass spectrum corroborated the
proposed structure.
As it was shown above for five-membered ring /-peptides, the
40 introduction of a peptide chain at C-3 on a hexopyranoside
system provokes a shielding of this nucleus and a deshielding of
the H-3. Accordingly, taking in comparison  values of C-3 for
compounds 25 and 26 (67.2 and 65.1 ppm, respectively) with that
of the same nucleus for compound 31 (49.9 ppm), and the C-3 
45 value for compound 28 (67.2 ppm) with that of compound 30
(51.3 ppm), a shielding of more than 15 ppm is observed (Table
2); on its turn,  value of H-3, moves from 4.35 or 4.37 ppm for
25 and 26, respectively, to 4.94 ppm for compound 31, and from
4.41 pm for 28 to 4.90 ppm for compound 30, being 0.5 ppm
50 aprox. the observed increase (Table 1).
1
TABLE 1. H NMR spectroscopic data for characteristic protons
in /-and /-hybrid peptides and their most relevant
15 precursors.a
Cp.
[ppm]
t
H-1
-
H-3
N-H
CH2
Gly
CO2Et CO2 Bu
residue
4.11dd
and
13
14b
15
4.68dd
4.14ddb
4.07dd
7.07t
4.23q
and
1.29t
-
-
-
-
4.07dd
-
3.56dd
and
3.43ddb
3.64dd
and
-
-
-
-
TABLE 2. 13C NMR spectroscopic data for characteristic carbons
in /-and /-hybrid peptides and their most relevant
precursors.a
3.52dd
3.42mc
3.50dd
and
3.99ddc
4.58-
-
-
-
-
-
16
6.43s br
3.77dd
and
1.43s
Cp.
[ppm]
4.53m
t
C-1
C-3
C-6
CH2
Gly
CO2Et
CO2 Bu
3.40dd
3.35-
3.72dd
3.58dc
6.0s brc
6.90t
4.33dddc
4.24dd
-
1.39sc
-
3.31mc
residue
41.0
22d
26
4.92d
4.07dd
and
4.21q
and
1.26t
4.26q
and
1.31t
-
13
167.3
63.2
63.1
169.3,
61.8,
14.2
-
-
3.94dd
4.10dd
5.11-
4.37dd
7.17t
-
14b
15
72.5
72.7
66.4
66.7
71.3
71.7
-
-
-
-
5.10m
-
28
30b
5.07d
5.07d
4.41t
-
-
-
72.1c 65.3c 70.4c
-
-
-
-
4.90m
7.70d
and
3.96dd
and
-
1.43s
16b 72.9b 53.9b 72.0b
44.9b
157.0,
79.6,
28.6b
5.30 t
7.26-
7.22s
and
3.74dd
4.09dd
and
71.9c 52.4c 70.7c
43.4c
-
31
5,11m
4.94t
4.22q
and
1.41s
155.8,
78.1,
28.1c
-
3.79dd
1.28t
5.49t
22d
26
96.8
97.4
65.0
65.1
167.8
171.7
41.1
40.8
169.5,
61.7,
14.2
169.1,
60.5,
14.1
-
a At 500 MHz in CDCl3, unless otherwise indicated; b in acetone-d6; c in
DMSO-d6; d at 300 MHz.
-
On the other hand, coupling of compound 27 with protected
20 glycine under the above mentioned conditions easily achieved the
/-glycopeptide 31 which has a structure of type 5. The MS and
28
30b
97.2
97.8
67.2
51.3
170.8
172.7
-
-
1
NMR data of 31 corroborated the assigned structure. Thus, H
44.6
-
157.0
80.5
28.4
NMR spectrum (Table 1) of compound 31 showed two amine
proton signals, among them that of the highest  value (broad

Page 7 of 12
Organic & Biomolecular Chemistry
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31b
97.8
49.9
171.5
60.4,
44.5
169.4,
155.9,
80.5,
28.3
procedure.25a Preparation of 2,5-anhydro-3-azido-3-deoxy-
aldehydo-D-altrose dimethylacetal (10) and subsequent
acetylation to give 4,6-di-O-acetyl-2,5-anhydro-3-azido-3-deoxy-
55 aldehydo-D-altrose dimethylacetal (11) were carried out as
previously described.25a
61.7,
14.1
a At 125.7 MHz in CDCl3, unless otherwise indicated; b in acetone-d6; c in
DMSO-d6;  at 75.8 MHz.
4,6-Di-O-acetyl-2,5-anhydro-3-azido-3-deoxy-D-altronic
acid (12). Procedure (a):25a Compound 11 (111 mg, 0.299 mmol)
60 was dissolved in a 9:1 TFA/H2O mixture (3.1 mL) and the
solution was allowed to stand at room temperature for 1 h. The
reaction was poured into ice-water (100 mL) and extracted with
CH2Cl2 (4 × 20 mL). The combined organic layers were
successively washed with saturated sodium hydrogen carbonate
65 and brine, then dried (Na2SO4) and concentrated. The residue
(crude 13) was dissolved in ether (2.3 mL) and cooled to -30°C.
Conclusions
This work provides a straightforward carbohydrate-based design
of novel enantiopure, cyclic /- and /-hybrid peptides useful
as potential monomer structure building blocks for foldamers,
chiral catalysts, and self-assembling nanostructured LC phases.
An economic, diversity-oriented strategy to access both five- and
six-membered ring heterogeneous backbone subunits has been
10 developed. Five-membered ring /-peptides were synthesized
via formyl C-glycofuranosides, easily available from hexose-
derived azido-2-equatorial-OH-glycopyranosides by DAST-
promoted ring contraction. A regioselective oxidation with
TEMPO at the primary 6-OH group of hexose-derived azido-
15 glycopyranosides as the key step, afforded two- and three residue
/-peptides, having a six-membered ring, in good yields and
under very simple experimental conditions. Our methodology: 1)
offers chemical efficiency and operational simplicity, starting
from readily inexpensive sugar derivatives; 2) allows complete
20 stereocontrol, and up to four or five contiguous stereocenters can
5
This
solution
was
treated
with
aqueous
sodium
dichromate/sulphuric acid (Jones' reagent, 3.6 mL, 2.35 mmol)
and the temperature was left to reach to reach room temperature.
70 The organic solvent was evaporated under reduced pressure and
the residue was filtered through a silica gel path by using ether
(100 mL) and then ethyl acetate (150 mL) as eluents, to give pure
12 (44 mg, 65%). Procedure (b): A solution of 18 (50 mg, 0.183
mmol) in ether (2.5 mL) was cooled to -30 ºC. This solution was
75 treated with aqueous sodium dichromate/sulphuric acid (Jones'
reagent, 3.6 mL, 2.35 mmol) and the temperature was left to
reach room temperature. The organic solvent was evaporated
under reduced pressure and the residue was filtered through a
silica gel path by using ether (100 mL) and then ethyl acetate
80 (150 mL) as eluents, to give pure 12 (38 mg, 72%). Compound
12: Rf 0.37 (1:4 acetone/ether); []D25 +40.2 (c 0.50, CH2Cl2); IR
be assembled, that being
a remarkable improvement in
comparison with related systems previously described; 3) in
addition to the diversity supplied by introducing different
available -amino acids, sugar stereodiversity can be also
25 exploited.

max 3300 (OH), 2120 (N3), 1746 (C=O), 1231 and 1119 cm-1 (C–
1
O); H NMR (500 MHz, CDCl3)  5.19 (dd, 1H, J3,4 = 5.0, J4,5
=
Experimental
8.0, H-4), 4.77 (d, 1H, J2,3 = 4.5, H-2), 4.69 (dd, 1H, H-3), 4.45
85 (ddd, 1H, J5,6 = 2.8, J5,6’ = 4.0, H-5), 4.39 (dd, 1H, J6,6’ = 12.5, H-
6), 4.15 (dd, 1H, H-6’), and 2.18 and 2.10 (each s, each 3H, 2
COMe); 13C NMR (125.7 MHz)  172.0 (COOH), 170.7 and
170.4 (2 COMe), 78.3 and 78.2 (C-2 and C-5), 73.2 (C-4), 62.8
and 62.7 (C-3 and C-6), and 20.9 and 20.4 (2 COMe); CIHRMS:
90 m/z 288.0836 (calcd for C10H13N3O7 + H+: 288.0832).
General methods
All chemicals were purchased and used without further
purification. Evaporations were conducted under reduced
30 pressure. TLC was performed on aluminium sheets coated with
Kieselgel 60 F254; detection of compounds was accomplished
with UV light (254 nm) and by charring with 10% H2SO4 or an
anisaldehyde reagent. Silica gel 60 (230 mesh) was used for
preparative column chromatography. Optical rotations were
35 measured at room temperature in 1-cm or 1-dm tubes. Infrared
(IR) spectra were recorded on a FTIR spectrophotometer. 1H (and
13C NMR) spectra were recorded at 300 (75.5 for 13C) and 500
(125.7 for 13C) MHz instruments, using the solvent peak as
internal reference; chemical shifts () are expressed in ppm from
40 TMS; coupling constants (J), in Hz. 2D COSY, and 1H−13C
HMQC experiments were used to assist NMR assignments. Mass
spectra were recorded by using either CI, EI, or FAB techniques
at 70 eV for EI and at 150 eV for CI. FAB mass spectra were
recorded by using a thioglycerol matrix. HRMS measurements
45 were made with resolutions of 10000, by using a magnet sector
analyzer.
4,6-Di-O-acetyl-2,5-anhydro-3-azido-3-deoxy-N-
(ethoxycarbonyl-methyl)-α-D-altruronamide (13). Compound
12 (37 mg, 0.129 mmol) was dissolved, under argon atmosphere,
95 in CH2Cl2 (3 mL); to this solution, ethyl glycinate hydrochloride
(26.9 mg, 0.193 mmol) and hydroxy-benzotriazole (HOBt, 17
mg, 0.193 mmol) were added, and the mixture was cooled to 0
ºC. After 10 min, DIPEA (33 L) was added and, 10 min later, N-
ethyl-N’-(3-dimethylaminopropyl)-carbodiimide hydrochloride
100 (EDCI, 37 mg, 0.193 mmol) was also added to the mixture,
which was left to reach room temperature under stirring. After 20
h, the mixture was diluted with CH2Cl2 (20 mL) and successively
washed with 1M HCl (40 mL), saturated aqueous solution of
potassium carbonate (40 mL), water (40 mL), and saturated
105 aqueous solution of NaCl (40 mL); the organic layer was dried
(Na2SO4) and concentrated at reduced pressure to give the
(1R and 1S)-2,5-Anhydro-3-azido-4,6-O-benzylidene-3-deoxy-1-
fluoro-1-O-methyl-D-altritol (9), as a separable epimeric mixture
9a and 9b, were obtained from methyl 3-azido-4,6-O-
50 benzylidene-3-dideoxy--D-allopyranoside (8)24 in one step by
reaction with DAST in acetonitrile following the reported
chromatographically homogeneous (Rf 0.53, 10:1 CH2Cl2
MeOH) compound 13 (32 mg, 67%) as a syrup; []D +52 (c
0.66, CH2Cl2). IR max 3298 (NH), 2114 (N3), 1740 (CO ester),
:
24
Org. Biomol. Chem., 2012, [vol], 00–00

Organic & Biomolecular Chemistry
Page 8 of 12
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1674 (CO amide), 1123 (C-O) cm-1. 1H NMR (500 MHz, CDCl3,
(125.7 MHz, acetone-d6)  139.7-128.4 (Ph), 84.8 (C-5), 84.5 (C-
 ppm, J Hz)  7.07 (dd br, 1H, JNH,CH2a = 5.0, NH), 5.22 (dd, 1H, 60 4), 80.3 (C-2), 73.8 (CH2Ph), 72.7 (C-1), 71.7 (C-6), 66.7 (C-3),
J4,5 = 8.5, J3,4 = 4.5, H-4), 4.68 (dd, 1H, J2,3 = 4.5, H-3), 4.62 (d,
59.1 (OMe). 13C NMR (125.7 MHz, DMSO-d6)  132.2-127.9
(Ph), 83.4 (C-5), 83.0 (C-4), 79.1 (C-2), 72.6 (CH2Ph), 72.1 (C-
1), 70.4 (C-6), 65.3 (C-3), 58.7 (OMe).CIHRMS m/z 268.1550,
calcd for C14H21NO4 + H: 268.1549.
1H, H-2), 4.40-4.36 (m, 1H, H-5), 4.36 (dd, 1H, J6,6’ = 12.5, J5,6
=
5
2.5, H-6), 4.23 (q, 2H, J = 7.0, Et), 4.13 (dd, 1H, J5,6’ = 4.0, H-
6’), 4.11 (dd, 1H, Jgem = 18.0, NHCHa ), 4.07(dd, 1H, NHCHb ),
2
2
2.16, 2.09 (2s, each 3H, COMe), 1.29 (t, 3H, Et). 13C NMR
(125.7 MHz, CDCl3)  170.6, 170.2 (COMe), 169.3 (COOEt),
167.3 (CONH), 80.0 (C-2), 78.0 (C-5), 73.6 (C-4), 63.2 (C-3),
65
2,5-Anhydro-3-N-terc-butoxycarbonylamino-6-O-benzyl-3-
deoxy-1-O-methyl-D-altritol (16). A solution of compound 14
(105 mg, 0.359 mmol) in dry THF (3.5 mL) was treated with
triphenylphosphine (103.2 mg, 0.393 mmol). The mixture was
70 allowed to stand at room temperature until monitoring by TLC
(3:1 EtOAc/hexane) showed that the reaction was completed (8
h). Then 0.5 mL of water were added and the mixture was stirred
for 20 h at room temperature. The solvent was evaporated under
reduced pressure and the residue dried under vacuum. This crude
10 63.1 (C-6), 61.8 (OCH2CH3), 41.0 (NHCH2), 20.9, 20.3 (COMe),
14.2 (OCH2CH3). CIHRMS m/z 373.1349, calcd for C14H20N4O8
+ H: 373.1359.
2,5-Anhydro-3-azido-6-O-benzyl-3-deoxy-1-O-methyl-D-
15 altritol (14). A solution of 9 (105 mg, 0.340 mmol) in dry THF
(4.8 mL) containing 3Å molecular sieves, was treated with
NaCNBH3 (273 mg, 4.35 mmol). The mixture was stirred for 15 75 product dissolved in dry CH2Cl2 (2.2 mL) was added to a mixture
min, and then Et2O/HCl (3.5%, 6 mL) was added. After 5 min,
the reaction was diluted with H2O (20 mL) and CH2Cl2 (20 mL).
20 After separation, the organic layer was successively washed with
sat. aq NaHCO3 (50 mL) and brine (50 mL), dried (Na2SO4), and
previously prepared as follows: Boc-Gly-OH (90.4 mg, 0.516
mmol) was dissolved, under argon atmosphere, in dry CH2Cl2
(2.2 mL), and HOBt (105 mg, 0.778 mmol) and DIPEA (90 L,
0.516 mmol) were successively added. The mixture, cooled to 0
concentrated. Column chromatography (EtOAc/hexane 1:3) gave 80 ºC, was treated with EDCI (150 mg, 0.778 mmol) at the same
24
pure 14 (64 mg, 64%). []D +16.2 (c 0.63, CH2Cl2). IR max
temperature for 10 min. The reaction mixture containing the
crude amine was left to reach room temperature for 20 h. The
mixture was then diluted with CH2Cl2 (30 mL) and successively
washed with 2% HCl (50 mL), saturated aqueous solution of
3345 (OH), 2108 (N3), 1121 and 1006 (C-O-C) cm-1. H NMR
25 (500 MHz, acetone-d6,  ppm, J Hz)  7.36-7.26 (m, 5H, Ph),
4.75 (s br, 1H, OHC4), 4.55 (s, 2H, CH2Ph), 4.55-4.53 (m, 1H, H-
1
4), 4.17 (ddd, 1H, J1,2 = J1’,2 = 5.7, J2,3 = 3.7, H-2), 4.14 (dd, 1H, 85 potassium carbonate (50 mL), water (50 mL), and saturated
J3,4 = 4.2, H-3), 3.93 (ddd, 1H, J4,5 = 7.5, J5,6’ = 4.5, J5,6 = 3.0, H-
5), 3.65 (dd, 1H, J6,6’ = 11.0, H-6), 3.58 (dd, 1H, H-6’), 3.56 (dd,
aqueous solution of NaCl (50 mL); the organic layer was dried
(anhydrous sodium sulfate) and concentrated at reduced pressure.
The residue was purified by column chromatography (Rf 0.42,
10:1 CH2Cl2/acetone) to give pure 16 (125 mg, 82%) as a syrup.
30 1H, J1,1’ = 10.0, H-1), 3.43 (dd, 1H, H-1’), 3.31 (s, 3H, OMe). 13
C
NMR (125.7 MHz, acetone-d6)  139.8-128.2 (Ph), 82.0 (C-5),
78.4 (C-2), 74.6 (C-4), 73.8 (CH2Ph), 72.5 (C-1), 71.3 (C-6), 66.4 90 []D21 +37.2 (c 0.77, acetone). IR max 3392 (NH, OH), 1719 (CO
(C-3), 59.1 (OMe). CIHRMS m/z 294.1462, calcd for C14H19N3O4
+ H: 294.1454.
carbamate), 1605 (CO amide), 1595 (NCO), 1051 (C-O-C) cm-
1.1H NMR (500 MHz, acetone-d6,  ppm, J Hz)  7.36-7.33 (m,
5H, Ph), 7.09 (d, 1H, JNH,3 = 7.0, C-CO-NH), 6.43 (s br, 1H, O-
CO-NH), 4.58-4.53 (m, 1H, H-3), 4.57 and 4.58 (each 2d, 1H,
35
2,5-Anhydro-3-amino-6-O-benzyl-3-deoxy-1-O-methyl-D-
altritol (15). A solution of compound 14 (35.7 mg, 0.122 mmol) 95 JH,H’ = 12.9, CH2Ph), 4.45 (d, 1H, JOH,4 = 8.0, OHC4), 4.31 (ddd,
in dry THF (1.5 ml) was treated with triphenylphosphine (32 mg,
0.122 mmol). The mixture was allowed to stand at room
40 temperature until monitoring by TLC (3:1 EtOAc/hexane)
1H, J2,3 = 8.0, J1’,2 = 4.5, J1,2 = 3.0, H-2), 4.17-4.14 (m, 1H, H-4),
4.01 (ddd, 1H, J5,6 = J5,6’ = 4.0, J4,5 = 3.0, H-5), 3.77 (dd, 1H, Jgem
= 16.5, JNH,CH2a = 6.0, NHCHa2), 3.72 (dd, 1H, JNH,CH2b = 6.0,
showed that the reaction was completed (8 h). Then 200 L of
NHCHb ), 3.55 (dd, 1H, J6,6’ = 10.5, H-6), 3.52 (dd, 1H, H-6’),
2
water were added and the mixture was stirred for 20 h at room 100 3.50 (dd, 1H, J1,1’ = 10.5, H-1), 3.40 (dd, 1H, H-1’), 3.35 (s, 3H,
1
temperature. The solvent was evaporated under reduced pressure,
and the residue was purified by column chromatography (Rf 0.48,
45 5:1 CH2Cl2/MeOH) to give pure 15 (31.0 mg, 95%). []D +0.5
OMe), 1.43 (s, 9H, CMe3). H NMR (500 MHz, DMSO-d6, 
ppm, J Hz)  7.37-7.26 (m, 5H, Ph), 7.29-7.26 (m, 1H, C-CO-
NH), 7.08 (t br, 1H, JNH,CH2Gly = 6.0, O-CO-NH), 5.36 (d, 1H,
25
(c 1.2, acetone). IR max 3325 (NH, OH), 1113 and 1071 (C-O-C)
JOH,4 = 8.0, OHC4), 4.51 (s, 2H, CH2Ph), 4.33 (ddd, 1H, J3,NH =
1
cm-1. H NMR (500 MHz, acetone-d6,  ppm, J Hz)  7.35-7.33 105 8.5, J2,3 = J3,4 = 5.9, H-3), 4.13 (ddd, 1H, J1,2 = 6.2, J1’,2 = 4.1, H-
(m, 5H, Ph), 4.56 (dd, 1H, J3,4 = 6.5, J4,5 = 1.5, H-4), 4.56, 4.28
2), 4.05 (ddd, 1H, J4,5 = 5.7, H-4), 3.91 (ddd, 1H, J5,6 = 3.8, J5,6’ =
(2d, 1H each, JH,H’ = 12.0, CH2Ph), 4.15 (ddd, 1H, J1,2 = J1’,2
50 J2,3 = 5.0, H-2), 4.07 (dd, 1H, H-3), 3.99 (ddd, 1H, J5,6 = J5,6’
5.0, H-5), 3.73 (s, 1H, OH), 3.64 (dd, 1H, J1,1’ = 10.8, H-1), 3.55
=
=
5.3, H-5), 3.58 (d, 2H, NHCH2), 3.52 (dd, 1H, J6,6’ = 10.6, H-6),
3.46 (dd, 1H, H-6’), 3.35-3.31 (m, 2H, H-1, H-1’), 3.21 (s, 3H,
OMe), 1.39 (s, 9H, CMe3). 13C NMR (125.7 MHz, acetone-d6) 
(dd, 1H, J6,6’ = 10.8, H-6), 3.52 (dd, 1H, H-1’), 3.52 (dd, 1H, H- 110 170.5, (N-CO-C), 157.0 (N-COO), 139.6-128.2 (Ph), 85.2 (C-5),
6’), 3.30 (s, 3H, OMe). 1H NMR (500 MHz, DMSO-d6,  ppm, J
Hz)  7.37-7.28 (m, 5H, Ph), 5.33 (s br, 1H, OHC4), 4.51, 4.48
79.6 (CMe3), 78.9 (C-2), 73.8 (CH2Ph), 73.1 (C-4), 72.9 (C-1),
72.0 (C-6), 59.3 (OMe), 53.9 (C-3), 44.9 (CH2NHCO), 28.6
(CMe3). 13C NMR (125.7 MHz, DMSO-d6)  169.6, (N-CO-C)
155.8 (N-COO), 138.3-127.3 (Ph), 82.0 (C-5), 78.1 (CMe3), 77.7
55 (2d, 1H each, JH,H’ = 12.0, CH2Ph), 4.41 (dd, 1H, J3,4 = 6.5, J4,5
=
1.5, H-4), 4.04 (ddd, 1H, J1,2 = 7.0, J1’,2 = J2,3 = 5.5, H-2), 3.99
(dd, 1H, H-3), 3.93 (ddd, 1H, J5,6 = J5,6’ = 5.5, H-5), 3.55-3.42 115 (C-2), 72.3 (CH2Ph), 71.9 (C-1), 70.9 (C-4), 70.7 (C-6), 58.2
(m, 4H, H-1, H-1’, H-6, H-6’), 3.26 (s, 3H, OMe). 13C NMR
(OMe), 52.4 (C-3), 43.4 (CH2NHCO), 28.1 (CMe3). CIHRMS

Page 9 of 12
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m/z 425.2291, calcd for C21H32N2O7 + H: 425.2288. Anal. calcd
and trichloro-isocyanuric acid (TCCA, 2 portions, each of 158
for C21H32N2O7: C, 59.42; H, 7.60; N, 6.60. Found: C, 59.12; H, 60 mg, 0.68 mmol in all, at 10 min interval). The mixture was left to
7.45; N, 6.72.
reach room temperature under stirring. After 1 h, the complete
transformation of the starting product was observed (TLC, 5:1
CH2Cl2/MeOH), and the suspension was then filtered through
Celite and the filtrate was treated with saturated aqueous sodium
5
4,6-Di-O-acetyl-2,5-anhydro-3-azido-3-deoxy-D-altrose
(17), and 4,6-di-O-acetyl-2,5-anhydro-3-azido-3-deoxy-D-
altritol (18).25a Diastereomeric mixture 9 (100 mg, 0.324 mmol) 65 hydrogencarbonate (30 mL) and washed with ethyl acetate (3 ×
was dissolved in a 9:1 TFA/H2O mixture (3. mL) and the solution
was allowed to stand at room temperature for 1 h. The reaction
10 was poured into an ice-water mixture (100 mL) and extracted
with CH2Cl2 (4 × 20 mL). The combined organic layers were
25 mL). The aqueous layer was acidified with 2 M HCl and
evaporated to dryness. The residue, crude product 20, was treated
with acetic anhydride (4 mL) in pyridine (4 mL). After 48 h at 4
ºC the mixture was poured onto ice-water (20 mL) to give a
evaporated under vacuum and the residue, without purification, 70 syrup that was extracted with ethyl acetate (3 × 20 mL). The
was dissolved in anhydrous pyridine (1 mL), cooled to 0 °C and
treated with acetic anhydride (1 mL). The reaction mixture was
15 stirred at room temperature for 20 h and was poured into an ice-
water mixture (100 mL) and extracted with CH2Cl2 (4 × 20 mL).
combined organic layers were washed with saturated aqueous
sodium hydrogencarbonate (2 mL), dried (anhydrous sodium
sulfate) and the solvent was evaporated to dryness, to give the
chromatographically homogeneous (Rf 0.10, 5:1 CH2Cl2/MeOH)
1
The combined organic layers were washed with saturated 75 compound 21 as a syrup (138.5 mg, 87%). H RMN (500 MHz,
aqueous sodium hydrogen carbonate, brine and dried (Na2SO4).
Evaporation of the solvent under reduced pressure afforded crude
20 17 (81.0 mg, 92%) as a chromatographically homogeneous oil.
This product was dissolved in 1,2-diclhoroethane (3 mL) and
CDCl3 ppm, J Hz)  5.19 (dd, 1H, J4,3 = 3.5, J4,5 = 10.0, H-4),
4.98 (m 2H, J1,2 = J2,3 = 2.0, H-1, H-2), 4.62 (d, 1H, J5,4 = 10.0,
H-5), 4.36 (t, 1H, J3,2 ≈ J3,4, H-3), 3.50 (s, 3H, OMe), 2.19 and
2.14 (2s, each 3H, COMe). 13C NMR (125.7 MHz, CDCl3): 
treated with imidazole (28 mg, 0.416 mmol) and sodium 80 171.3 (COOH), 170.0 and 169.7 (2 COMe), 97.1 (C-1), 68.3 (C-
triacetoxyborohydride (90.0 mg, 0.426 mmol). The reaction was
stirred at room temperature for 24 h and then was diluted with
25 sat. aq NaHCO3 (25 mL). The aqueous layer was extracted with
EtOAc (3 × 20 mL), and the combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure. Purification
of the residue by column chromatography (1:1 ether/hexane) gave
pure 18 (62 mg, 70% from 9).
2), 67.9 (C-4), 64.7 (C-3), 59.2 (C-5), 56.9 (OMe), 20.8 and 20.6
(2 COMe). CIHRMS m/z 324.1200, calcd for C14H17N3O6 + H:
324.1196.
85
Ethyl
[methyl
3-azido-2,4-di-O-acetyl-3-deoxy-α-D-
allopyranosid]uronyl -glycinate (22). Compound 21 (25 mg,
0.079 mmol) was dissolved, under argon atmosphere, in CH2Cl2
(3 mL); to this solution, ethyl glycinate hydrochloride (26.9 mg,
0.193 mmol) and HOBt (17 mg, 0.193 mmol) were added, and
30 Compound 17: Rf 0.37 (1:4 EtOAc/hexane); []D25 +40.9 (c 0.49,
CH2Cl2); IR max 2114 (N3), 1742 (C=O), 1233 and 1125 (C–O)
1
cm-1; H NMR (500 MHz, CDCl3,  ppm, J Hz)  9.63 (d, 1H, 90 the mixture was cooled to 0 ºC. After 10 min, DIPEA (33 L)
JCHO,2 = 1.5, CHO), 4.31 (dd, 1H, J3,4 = 5.0, J4,5 = 7.0, H-4), 4.69
(dd, 1H, J2,3 = 5.0, H-3), 4.46 (dd, 1H, H-2), 4.45 (m, 1H, H-5),
was added and, 10 min later, EDCI (37 mg, 0.193 mmol) was
also added to the mixture, which was left to reach room
temperature under stirring overnight. The mixture was then
diluted with CH2Cl2 (20 mL) and successively washed with 1M
35 4.39 (dd, 1H, J5,6 = 3.2, J6,6’ = 12.2, H-6), 4.15 (dd, 1H, J5,6’
=
4.2, H-6’), and 2.17 and 2.11 (each s, each 3H, 2 COMe); 13C
NMR (125.7 MHz, CDCl3)  199.2 (CHO), 170.6 and 170.3 (2 95 HCl (40 mL), saturated aqueous solution of potassium carbonate
COMe), 82.7 (C-2), 78.8 (C-5), 73.8 (C-4), 63.3 (C-3), 63.1 (C-
6), and 20.9 and 20.5 (2 COMe); CIHRMS: m/z 272.0892, calcd
40 for C10H13N3O6 + H: 272.0883).
(40 mL), water (40 mL), and saturated aqueous solution of NaCl
(40 mL); the organic layer was dried (Na2SO4) and concentrated
at reduced pressure to give the chromatographically
homogeneous (Rf 0.60, 3:1 EtOAc/hexane) compound 22 as
25
Compound 18: Rf 0.40 (4:1 EtOAc/hexane); []D +19.4 (c
0.72, CH2Cl2); IR max 3306 (OH), 2108 (N3), 1227 and 1119 (C– 100 syrup (21.4 mg, 67%). 1H RMN (300 MHz, CDCl3,  ppm, J Hz)
1
O) cm-1; H NMR (300 MHz, CDCl3,  ppm, J Hz)  5.22 (dd,
1H, J4,5 = 7.3, J3,4 = 5.2, H-4), 4.41 (dd, 1H, J2,3 = 4.8, H-3), 4.32
45 (dd, 1H, J6,6’ = 11.7, J5,6 = 3.0, H-6), 4.30–4.21 (m, 2H, H-2 and
H-5), 4.11 (dd, 1H, J5,6’ = 4.2, H-6’), 3.82 (d, 2H, J1 and 1’,2 = 6.0,
 6.90 (t, 1H, JNH,CH ≈ 4.5, NH), 5.12 (dd, 1H, J4,3 = 3.6, J4,5 =
9.9, H-4), 4.93 (dd 1H, J2,1 = 3.9, J2,3 = 4.2, H-2), 4.92 (d, 1H, J1,2
= 3.9, H-1), 4.24 (dd, 1H, J3,2 = J3,4 = 3.6, H-3), 4.47 (d, 1H, J5,4
= 9.9, H-5), 4.21 (q, 2H, Jethyl = 6.9, CH2CH3), 4.07 (dd, 1H,
H-1 and H-1’), 2.19 and 2.12 (each s, each 3H, 2 COMe), and 105 JCH,NH = 5.4, Jgem = 18.3, NHCHa ), 3.94 (dd, 1H, NHCHb ), 3.44
2
2
1.95 (br s, 1H, OH); 13C NMR (75.4 MHz, CDCl3)  170.8 and
170.5 (2 COMe), 79.7 and 77.3 (C-5 and C-2), 74.3 (C-4), 63.6
50 (C-6), 62.5 (C-3), 62.0 (C-1), and 20.9 and 20.5 (2 COMe);
CIHRMS: m/z 274.1026, calcd for C10H15N3O6 + H: 274.1039).
(s, 3H, OMe), 2.17 and 2.14 (2s, each 3H, COMe), 1.26 (t, 3H,
CH2CH3). 13C RMN (75.8 MHz, CDCl3):  169.9, 169.6 (COMe),
169.5 (COOEt), 167.8 (CONH), 96.8 (C-1), 68.6 (C-2), 68.0 (C-
4), 65.0 (C-3), 64.9 (C-5), 61.7 (OCH2CH3), 56.7 (OMe), 41.1
110 (NCH2CO2Et), 18.7, 17.5 (COMe), 14.2 (OCH2CH3). CIHRMS:
m/z 403.1467; calculated for C15H22N4O9 + H: 403.1465.
Methyl 3-azido-2,4-di-O-acetyl-3-deoxy-α-D-allopyranosid-
uronic acid (21).
A 15% aqueous solution of sodium
55 hydrogencarbonate (2 mL) was added to a solution of 19 (150
Methyl
3-azido-2-O-benzoyl-3-deoxy-α-D-allopyranoside
mg. 0.68 mmol) in acetone (5 mL). To this mixture, cooled to 0
(24). The acetal 23 (0.519 g, 1.26 mmol) was dissolved in a 7:3
ºC, the following reagents were successively added: sodium 115 mixture of acetic acid/H2O and heated under reflux for 30 min.
bromide (15.6 mg, 0.15 mmol), TEMPO (2.5 mg, 0.016 mmol),
Monitoring of the reaction (TLC, 1:2 EtOAc/hexane) was
Org. Biomol. Chem., 2012, [vol], 00–00

Organic & Biomolecular Chemistry
Page 10 of 12
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maintained until the complete conversion into a new compound.
JCH,NH = 5.5, Jgem = 9.5, -NHCH2CO2Et), 3.98 (dd, 1H, J4,3 = 3.5,
Solvents were co-evaporated with H2O and eventually with EtOH 60 J4,5 = 9.5, H-4), 3.48 (s, 3H, OMe), 1.31 (t, 3H, CH2CH3). 13C
to leave crystalline compound 24 (0.399 g, 98%); Rf 0.37 (3:1
RMN (125.7 MHz, CDCl3):

171.7 (CONR), 169.1
25
EtOAc/hexane); []D +26.5 (c 1, CH2Cl2); IR max 3453 (OH),
(CO2CH2CH3), 165.6 (OCOPh), 133.8, 130.8, 128.8, 128.6, 128.5
(5C-Ph), 97.4 (C-1), 69.7 (C-2), 68.8 (C-4), 65.1 (C-3), 61.9 (C-
5), 60.5 (OCH2CH3), 56.9 (OMe), 40.8 (NCH2CO2Et), 14.1
1
5
2110 (N3), 1720 (C=O), 1267 and 1093 (C–O-C) cm-1; H NMR
(300 MHz, CDCl3,  ppm, J Hz) 8.10, 7.51, 7.44 (m, 5H, Ph),
5.17 (t, 1H, J2,1  J2,3 = 3.9, H-2), 4.99 (d, 1H, J1,2 = 3.9, H-1), 65 (OCH2CH3). CIHRMS: m/z 423.1441, calcd for C18H22N4O7 + H:
4.39 (t, 1H, J2,3  J3,4 = 3.3, H-3), 3.89 (dd, 1H, J4,3 = 3.3, J2,1 423.1438.

J4,5 = 8.4, H-4), 3.94-3.79 (m, 3H, H-5, 2H-6), 3.42 (s, 3H, OMe).
10 13C NMR (75.8 MHz, CDCl3):  165.7 (OCOPh), 134.0, 130.0,
129.0 (Ph), 97.0 (C-1), 70.4 (C-2), 67.7 (C-5 or C-6), 66.4 (C-5
Ethyl (methyl 3-amino-2-O-benzoyl-3-deoxy-α-D-allo-
pyranosid)uronyl-glycinate (27). Pd/C catalyst (700 mg) was
or C-6), 62.2 (C-3), 61.9 (C-4), 56.2 (OMe). CIHRMS m/z 70 added to a solution of compound 26 (75 mg, 0.213 mmol) in
324.1200, calcd for C14H17N3O6 + H: 324.1196.
MeOH (10.2 mL), and hydrogen gas (~0.5 L) was bubbled at
atmospheric pressure and room temperature through the mixture
under shaking. Monitoring of the reaction (TLC) showed that the
reaction was completed after 12 min. The excess of hydrogen was
15
Methyl
3-azido-2-O-benzoyl-3-deoxy-α-D-allopyranosid-
uronic acid (25).
A 15% aqueous solution of sodium
hydrogencarbonate (13 mL) was added to a solution of 24 (973 75 displaced by an argon stream, the catalyst was filtered off (Celite
mg. 3.01 mmol) in acetone (30 mL). To this mixture, cooled to 0
ºC, the following reagents were successively added: NaBr (62.4
20 mg, 0.61 mmol), TEMPO (9 mg, 0.058 mmol), and TCCA (2
portions, each of 0.701 g, 6.02 mmol in all, at 10 min interval).
on a fritted glass filter) and the filter was washed with cold
methanol. Evaporation of the solvent gave 69 mg (quant. yield) of
chromatographically homogeneous crude 27, (Rf 0.10, 2:1
EtOAc/hexane), pure enough to be used for further
The mixture was left to reach room temperature under stirring. 80 transformation.
After 45 min, the suspension was filtered through Celite and the
filtrate was treated with saturated aqueous sodium carbonate (50
25 mL) and washed with EtOAc (3 × 25 mL). The aqueous layer
was acidified with 2 M HCl and extracted with EtOAc (2 × 100
Methyl (methyl 3-azido-2-O-benzoyl-3-deoxy--D-allo-
pyranosid)uronate (28). An argon stream was bubbled through a
solution of the alluronic acid derivative 25 (248.3 mg, 0.74
mL). The combined organic layers were dried (Na2SO4) and the 85 mmol) in 1:1 MeOH/MeCN, and a 2M solution of TMSCHN2
solvent was evaporated to dryness, to give compound 25 as syrup
(1.41 mL, 8.83 mmol) in hexane was added. Monitoring of the
reaction (TLC, 9:1 CH2Cl2/MeOH) indicated its completion after
4 h. The solvents were evaporated to give compound 28 (217.1
mg, 84%); Rf 0.8 (same elution system); IR max 3381 (OH),
25
(0.776 g, 77%); []D +48.2 (c 1, CH2Cl2); IR max 3197 (OH),
30 2111 (N3), 1715 (C=O), 1265 and 1092 (C–O-C) cm-1; 1H RMN
(500 MHz, CDCl3,  ppm, J Hz) 8.04, 7.53, 7.40 (m, 5H, Ph),
5.12 (d, 1H, J1,2  0.0, H-1), 5.04 (dd, 1H, J2,1  J2,3  0.0, H-2), 90 2111 (N3), 1724 (C=O), 1267 and 1173 (C–O-C) cm-1; 1H RMN
4.40 (d 1H, J5,4 = 9.5, H-5), 4.35 (br s, 1H, H-3), 4.01 (dd, 1H,
J4,3  0.0, J4,5 = 7.5, H-4), 3.43 (s, 3H, OMe). 13C RMN (125
35 MHz, CDCl3):  171.2 (COOH), 165.6 (OCOPh), 139.6, 130.2,
128.6, 128.5 (Ph), 97.2 (C-1), 69.4 (C-2), 68.8 (C-4), 67.2 (C-3),
(500 MHz, CDCl3,  ppm, J Hz) 8.11, 7.61, 7.48 (m, 5H, Ph),
5.19 (t, 1H, J2,1  J2,3 = 4.0, H-2), 5.07 (d, 1H, J1,2 = 4.0, H-1),
4.43 (br d 1H, H-5), 4.41 (t, 1H, J2,3  J3,4 = 3.3, H-3), 4.04 (dd,
1H, J4,3 = 3.5, J4,5 = 9.5, H-4), 3.86 (s, 3H, COOCH3), 3.49 (s, 3H,
61.1 (C-5), 56.7 (OMe). CIHRMS: m/z 338.0989, calcd for 95 OCH3). 13C RMN (125 MHz, CDCl3):  170.8 (CO2CH3), 165.7
C14H15N3O7 + H: 338.0988.
(OCOPh), 133.9, 130.3, 128.8, 128.7 (Ph), 97.2 (C-1), 69.5 (C-2),
68.4 (C-4), 67.2 (C-3), 61.2 (C-5), 56.8 (OCH3), 53.0 (CO2CH3).
CIHRMS m/z 352.1141, calcd for C15H17N3O7 + H: 352.1145.
40
Ethyl
allopyranosid)uronyl-glycinate (26). Compound 25 (25 mg,
0.074 mmol) was dissolved, under argon atmosphere, in CH2Cl2 100 Methyl (methyl 3-amino-2-O-benzoyl-3-deoxy--D-allo-
(methyl
3-azido-2-O-benzoyl-3-deoxy-α-D-
(3 mL); to this solution, ethyl glycinate hydrochloride (26.9 mg,
0.193 mmol) and HOBt (17 mg, 0.193 mmol) were added, and
45 the mixture was cooled to 0 ºC. After 10 min, DIPEA (33 L)
was added and, 10 min later, EDCI (37 mg, 0.193 mmol) was
pyranosid)uronate (29). Pd/C catalyst (900 mg) was added to a
solution of the azide 28 (148.7 mg, 0.42 mmol) in MeOH (20
mL). This mixture was shaken at room temperature and a
hydrogen stream was bubbled through it at atmospheric pressure.
also added to the mixture, which was left to reach the room 105 The pressure was maintained until monitoring of the reaction
temperature under stirring overnight. The mixture was then
diluted with CH2Cl2 (20 mL) and successively washed with 1M
50 HCl (40 mL), saturated aqueous solution of potassium carbonate
(40 mL), H2O (40 mL), and saturated aqueous solution of NaCl
(TLC, 9:1 CH2Cl2/MeOH) showed its completion after 2 h. The
excess of hydrogen was displaced by an argon stream, the
catalyst was filtered off (Celite on a fritted glass filter) and the
filter was washed with a few portions of cold MeOH. The filtrate
(40 mL); the organic layer was dried (Na2SO4) and concentrated 110 and washings were concentrated to dryness to leave 186 mg, (>
at reduced pressure to give the chromatographically
homogeneous (Rf 0.59, 2:1 EtOAc/hexane) compound 26 as a
55 syrup (21.3 mg, 82%). 1H RMN (500 MHz, CDCl3,  ppm, J Hz)
8.11, 7.61, 7.47 (m, 5H, Ph), 7.17 (t, 1H, JNH,CH ≈ 5.0, NH),
99%) of chromatographically homogeneous crude 29 (Rf 0.70
same elution system), pure enough to be used for further
transformation.
5.11-5.10 (m, 2H, H-2, H-1), 4.43 (d 1H, J4,5 = 10.0 H-5), 4.37 115 Methyl [methyl 2-O-benzoyl-3-(N-tert-butoxycarbonyl-
(dd, 1H, H-3), 4.26 (q, 2H, Jethyl = 7.0, CH2CH3), 4.10 (dd, 2H , glycylamido)-3-deoxy--D-allopyranosid]uronate (30). Boc-

Page 11 of 12
Organic & Biomolecular Chemistry
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Gly-OH (136 mg, 0.93 mmol) was dissolved, under argon
OCH3), 1,41 [s, 9H, C(CH3)3], 1.28 (t, 3H, Jethyl = 7.5, CH2CH3).
atmosphere, in dry CH2Cl2 (10 mL), and HOBt (167 mg, 1.24 60 13CRMN (125 MHz, CDCl3):

171.5 (C-6), 170.7
mmol) and DIPEA (161 L, 0.93 mmol) were successively
added. The mixture, cooled to 0 ºC, was treated with EDCI (237.7
mg, 1.24 mmol) at the same temperature for 10 min, after that, a
solution of the crude compound 29 (217.1 mg, 0.62 mmol) in dry
(NHCOCH2NHCO2But), 169.4 (CO2Et), 165.4 (OCOPh), 155.9
(N-CO2But), 133.6, 130.1, 129.0, 128.5, (Ph), 97.8 (C-1), 80.5
(CMe3), 69.0 (C-4), 66.7 (C-2), 61.7 (CH2CH3), 60.4 (O2C-
CH2NH), 56.4 (OCH3), 49.9 (C-3), 44.5 (CH2NH), 40.9 (C-5),
5
CH2Cl2 (10 mL) was added, and the reaction mixture was left to 65 28.3 [C(CH3)3], 14.1 (CH2CH3). CIHRMS: m/z 554.2355, calcd
reach the room temperature overnight. The mixture was then
diluted with CH2Cl2 (30 mL) and successively washed with 2%
for C25H35N3O11 + H: 554.2350.
10 HCl (50 mL), saturated aqueous solution of potassium carbonate
(50 mL), water (50 mL), and saturated aqueous solution of NaCl
(50 mL); the organic layer was dried (Na2SO4) and concentrated
at reduced pressure. Purification of the residue by column
chromatography (1:1 to 3:1 EtOAc/hexane) gave pure 30 (206
Acknowledgements
The authors thank the AECID (Projects A/023577/09 and
A/030422/10, and scholarship to one of them, S. Jatunov) and the
70 Junta de Andalucía (FQM 142 and Project P09-AGR-4597) for
financial support.
21
15 mg, 46%); Rf 0.38 (1:1 EtOAc/hexane); []D +20.2 (c 1,
CH2Cl2); IR max 3380 (NH, OH), 1719 (CO ester, carbamate),
1671 (CO amide), 1601 (NCO), 1068 (C-O-C) cm-1; 1H RMN
(500 MHz, CDCl3,  ppm, J Hz) 7.96, 7.51, 7.39 (m, 5H, Ph),
7.70 [br d, 1H, J3,NH = 6.5, NHCOCH2NHCO2C(CH3)3], 5.30 [t,
20 1H, JH,CH2 = 6.0, COCH2NHCO2C(CH3)3], 5,19 (t, 1H, J2,3 = J2,1
= 3.8, H-2), 5.07 (d, 1H, J1,2 = 3.4, H-1), 4.90 (m, 1H, J3,2 = J3,4
= 3.5, H-3), 4.24 (d, J3,4 = 10.0, H-5), 4.11 (dd, 1H, J4,3 = 3,7, J4,5
= 9.8, H-4), 3.96 (dd, 1H , Jgem = 15.0, -CH2aNHCO2But), 3.83
(s, 3H, COOCH3), 3,74 (dd, 1H, JCH2NH = 5.0 Jgem = 16.0, -
Notes and references
a Departamento de Química Orgánica, Facultad de Química, Universidad
de Sevilla, C/ Profesor García González 1, 41012 Sevilla, Spain. Fax:
75 +34954624960; Tel: +34954556868; E-mail: fcabrera@us.es
† Electronic Supplementary Information (ESI) available: NMR spectra of
all new compounds. See DOI: 10.1039/b000000x/
1
2
S. J. Fleishman, D. Baker, Cell 2012, 149, 262.
(a) C. M. Goodman, S. Choi, S. Shandler, W. F. DeGrado, Nat.
Chem. Biol. 2007, 3, 252; (b) T. Sawada, S. H. Gellman, J. Am.
Chem. Soc. 2011, 133, 7336.
80
25 CH2bNHCO2But), 3.50 (s, 3H, OCH3), 1,43 [s, 9H, C(CH3)3]. 13
C
3
4
S. Hecht, I. Huc, (Eds.) Foldamers: Strucutre, Properties, and
Applications, Wiley-VCH: Weinheim, Germany, 2007.
(a) S. H. Gellman, Acc. Chem. Res. 1998, 31, 173; (b) P. S. Corbin,
S. C. Zimmerman, J. Am. Chem. Soc. 2000, 122, 3779; (c) O.
Khakshoor, B. Demeler, J. S. Nowick, J. Am. Chem. Soc. 2007, 129,
5558; (d) E. R. Gillies, F. Deiss, C. Staedel, J.-M. Schmitter, I. Huc,
Angew. Chem. Int. Ed. 2007, 46, 4081; (e) Z.-T. Li, J.-L. Hou, C. Li,
Acc. Chem. Res. 2008, 41, 1343; (f) B. Gong, Acc. Chem. Res.
2008, 41, 1376; (g) W. S. Horne, S. H. Gellman, Acc. Chem. Res.
2008, 41, 1399; (h) Y. Yan, B. Qin, C. Ren, X. Chen, Y. K. Yip, R.
Ye, D. Zhang, H. Su, H. Zeng, J. Am. Chem. Soc. 2010, 132, 5869;
(i) L. Fischer, G. Guichard, Org. Biomol. Chem. 2010, 8, 3101; (j)
G. N. Tew, R. W. Scott, M. L. Klein, B. DeGrado, Acc. Chem. Res.
2010, 43, 30; (k) G. Guichard, I. Huc, Chem. Commun. 2011, 47,
5933; (l) Q. Gan, Y. Ferrand, C. Bao, B. Kauffmann, A. Grélard, H.
Jiang, I. Huc, Science 2011, 331, 1172; (m) B. Wu, C. Jia, X. Wang,
S. Li, X. Huang, X.-J. Yang, Org. Lett. 2012, 14, 684.
RMN (125 MHz, CDCl3):  172.7 (C-6), 169.9 (OCOPh), 165.3
(NHCOCH2), 157.0 (N-COOBut), 133.7, 130.2, 129.1, 128.7,
128.0 (Ph), 97.8 (C-1), 80.5 (CMe3), 69.5 (C-4), 68.4 (C-5), 66.9
(C-2), 56.4 (OCH3), 52.9 CO2CH3), 51.3 (C-3), 44.6 (CH2NH),
30 28.4 [C(CH3)3]. CIHRMS: m/z 483.1958, calcd for C22H30N2O10
+ H: 483.1979.
85
90
Ethyl [methyl 2-O-benzoyl-3-(N-tert-butoxycarbonyl-gly-
cylamido)-3-deoxy-α-D-allopyranosid]uronyl-glycinate (31).
35 Boc-Gly-OH (90.4 mg, 0.516 mmol) was dissolved, under argon
atmosphere, in dry CH2Cl2 (2.2 mL), and HOBt (105 mg, 0.778
mmol) and DIPEA (90 L, 0.516 mmol) were successively
added. The mixture, cooled to 0 ºC, was treated with EDCI (150
mg, 0.778 mmol) at the same temperature for 10 min, after that, a
40 solution of the crude compound 27 (69 mg, 0.213 mmol) in dry
CH2Cl2 (2.2 mL) was added, and the reaction mixture was left to
the room temperature overnight. The mixture was then diluted
with CH2Cl2 (30 mL) and successively washed with 2% HCl (50
mL), saturated aqueous solution of potassium carbonate (50 mL),
45 H2O (50 mL), and saturated aqueous solution of NaCl (50 mL);
the organic layer was dried (Na2SO4) and concentrated at reduced
pressure to give, after column chromatography (2:1
EtOAc/hexane), compound 31 (66 mg, 56%) as a syrup; Rf 0.11
95
5
6
(a) W. S. Horne, S. H. Gellman, Acc Chem Res. 2008, 41, 1399; (b)
L. Guo, A. M. Almeida, W. Zhang, A. G. Reidenbach, S. H. Choi, I.
A. Guzei, S. H. Gellman, J. Am. Chem. Soc. 2010, 132, 7868; (c) J.
L. Price, W. S. Horne, S. H. Gellman, J. Am. Chem. Soc. 2010, 132,
12378.
W. S. Horne, L. M. Johnson, T. J. Ketas, P. J. Klasse, M. Lu, J. P.
Moore, S. H. Gellman, Proc. Natl. Acad. Sci. U.S.A. 2009, 106,
14751.
100
105
110
115
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25
(same elution system); []D +13.4 (c 1, CH2Cl2); IR max 3377
50 (NH, OH), 1718 (CO carbamate), 1671 (CO amide), 1601
(NCO), 1069 (C-O-C) cm-1. 1H RMN (500 MHz, CDCl3,  ppm, J
Hz) 8.00, 7.55, 7.43 (m, 5H, Ph), 7.26-7.22 (br s, 1H,
NHCH2CO2Et), 5.49 (t, 1H, JH,CH2 = 6.0, CONHCH2NH), 5.11
(br m, 2H, H-2, H-1), 4.94 (br t, 1H, J3,4 = 4.0, H-3), 4.22 (q, 2H,
55 Jethyl = 7,0, CH2CH3), 4.20 (d, 1H, J5,4 = 7.5, H-5), 4.09 (dd, 2H,
JH,NH = 6.0, Jgem = 14.5, -NHCH2aCO2Et, -CH2aNHCO2But), 3.97
(dd, 1H, J4,3 = 4.0, J4,5 = 10.0, H-4), 3,79 (dd, 2H, JCH2NH = 5.5
Jgem = 17, -NHCH2bCO2Et, -CH2bNHCO2But), 3.49 (s, 3H,
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