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7
Sugar Amino Acids
7.1
Introduction
A recognized strategy in drug discovery for generating new bioactive molecules takes into
account the vast array of natural products and fundamental building blocks used by nature,
like amino acids, sugars and nucleosides, to produce new chemical entities with multifunctional groups anchored on a single framework as the starting point for the creation of new
molecules. Sugar amino acids (SAAs) represent an important class of templates deriving
from the chiral pool that have attracted noteworthy interest in the area of peptidomimetics.
Sugar amino acids [1] are defined as carbohydrates possessing at least one amino and one
carboxylic functional group directly attached to the cyclic sugar moiety. Thus, such compounds represent an important class of building blocks for the generation of peptide scaffolds and constrained peptidomimetics, owing to the presence of a relatively rigid furanoid
or pyranoid ring decorated with space-oriented substituents. Much effort has been devoted
during last the two decades to expanding the chemical diversity of this class of hydroxylated
cyclic amino acids. Specifically, SAAs have been synthesized mainly as furanoid or pyranoid compounds, and both cyclic and bicyclic scaffolds have been reported (Figure 7.1).
There are several advantages to using SAAs as building blocks:
• These molecules possess the typical rigid furan and pyran rings as of carbohydrates,
which make them ideal candidates as non-peptide scaffolds for peptidomimetic
chemistry.
• They can be easily incorporated into peptide sequences by virtue of their carboxylic and
amino functional groups according to standard solid- or solution-phase peptide synthesis
methods.
• These compounds take advantage of the structural diversities of carbohydrate molecules,
as the presence of several stereocenters gives access to a wide array of isomers that can
be used to create combinatorial libraries of SAA-based molecular frameworks.
• The protected/unprotected hydroxyl groups on the sugar rings can be exploited to modulate the hydrophobic/hydrophilic nature of such molecular assemblies.
Peptidomimetics in Organic and Medicinal Chemistry: The Art of Transforming Peptides in Drugs, First Edition.
Andrea Trabocchi and Antonio Guarna.
© 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.
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Peptidomimetics in Organic and Medicinal Chemistry
O
(OH)k
H2N
O
(OH)k
CO2H H2N
m
n
CO2H
m
n
n = 0,1
m = 0,1
k = 0,3
pyranoid-SAA
furanoid-SAA
Figure 7.1 General structure of furanoid (five-membered ring) and pyranoid (six-membered
ring) sugar amino acids
Generally, the amino group is introduced by azidolysis of a hydroxyl group followed
by reduction and protection of the resulting amine, although cyanide and nitro equivalents
have been also reported. The carboxylic group is usually obtained by oxidation of a primary alcohol; in addition, hydrolysis of cyanide or direct insertion of CO2 have been also
described.
A quite recent compendium by Fleet and Overhand reported on the panorama of SAAs,
differing in ring size and further arranged by the amino acid class depending on the relative
orientation of the amino and carboxylic groups in the molecule [2]. Accordingly, a similar
description of the class of SAAs is presented, taking into account the amino acid subclass
and the furanoid or pyranoid structure within each amino acid group.
7.2
7.2.1
𝛂-SAAs
Furanoid 𝛂-SAAs
Furanoid α-SAAs have been reported mainly by Fleet and colleagues starting from the
mid-1990s. The common features of these molecules, possessing the furanoid scaffold, is to
have the carboxylic and amino functional groups installed at C1 in place of the hemiacetalic
moiety (Figure 7.2).
Dondoni and collaborators reported in 1994 [3] a general synthesis to anomeric
furanoid-based α-amino acids taking into account the azido group as a protecting group
for the amine. This synthesis considered the use of a thiazolyl ketol acetate species as
the key intermediate in the formylation of the sugar moiety at the anomeric position.
Starting from the addition of 2-lithiothiazole to the lactone, and subsequent acetylation,
the corresponding α- or β-anomer 1 (Scheme 7.1) was treated with trimethylsilyl triflate
(TMSOTf) and trimethylsilyl azide (TMSN3 ) to give the corresponding α- and β-azido
glycosides α-2 or β-2 in high yield and stereospecificity. Subsequent manipulation of this
R
O α NH2
1 CO2H
HO
OH
R = H, CH3, CH2OH,
CH(OH)CH2OH
Figure 7.2
General structure of furanoid α-SAAs
Sugar Amino Acids
S
O
O
O
O
S
O
N
OAc
O
NaBH4
N3
TMSOTf
O
O
1
HgCl2
O
2
O
CHO
O
O
N3
O
TfOMe
N
O
TMSN3
139
O
Ag2O, then
diazomethane
CO2Me
O
O
O
N3
O
O
H2, Pd/C
isolated as crude
3
4
O
O α CO2Me
O
1 NH2
O
O
5
Scheme 7.1 Synthetic approach to anomeric furanoid-based α-amino acids using thiazolyl
ketol acetate species
species resulted in the formylated derivative 3, which was subjected to oxidation with
Ag2 O, followed by esterification with diazomethane, and final catalytic hydrogenation
over Pd/C catalysis to give the final furanoid α-amino acid 5, as the α- or β-anomer,
depending on the stereochemistry of starting thiazolyl ketol acetate. This approach was
also reported for a galacto-derived pyranoid species (see Scheme 7.6 below).
Similarly, Fleet and coworkers obtained α-SAAs bearing the amino and carboxylic functions at the anomeric position through the corresponding azido and methyl ester functionalities as the protected forms (Scheme 7.2). The approach from δ-lactones considered the
process of ring contraction, followed by introduction of the azido group after a bromination reaction at the α-position of the ester group [4]. This synthetic strategy is based upon
the propensity of 2-O-trifluoromethanesulfonates of carbohydrate lactones to ring contract
in basic or acidic methanol to afford the corresponding highly substituted tetrahydrofuran
(THF) carboxylates. These compounds can be regioselectively brominated and the bromine
subsequently displaced with sodium azide to give access to a range of anomeric furanoid
α-SAAs, after further chemical manipulation.
A similar approach was also applied for the generation of l-rhamnose mimetics [5].
Specifically, ring contraction of readily available δ-1actones provided a short route to
the synthesis of both epimers of rhamnofuranosides, followed by radical bromination to
give access to the corresponding α-azido carboxylates. The Kiliani chain extension of
isopropylidene-rhamnose 6 was taken into account for the epimeric δ-lactones. Esterification of the major isomer 7 with trifluoromethanesulfonic anhydride (Scheme 7.3)
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Peptidomimetics in Organic and Medicinal Chemistry
O
RO
O
RO
ring
contraction
O
CO2Me
RO
OTf
RO
OR
OR
1. α-bromination
2. azide displacement
1
O 1 CO2R
2
α NHR functionalization
HO
HO
CO2Me
O
RO
OH
N3
RO
OR
Scheme 7.2 General approach to furanoid α-SAAs via ring contraction of carbohydrate
δ-lactones
O
OH
Kiliani chain extension
OH
HO
O
RO
O
OH
O
OH
6
O
7: R = H
8: R = Tf
triflate
formation
ring
contraction
O 1 N3
azide
α CO2Me displacement
HO
O
O
11
X
O
CO2Me
HO
O
radical
bromination
O
9: X = H
10: X = Br
Scheme 7.3 α-SAA from L-rhamnose
gave the corresponding triflate 8, which evolved to the corresponding THF 9 in 41%
overall yield upon treatment with potassium carbonate in methanol. Radical bromination
of ester 9 by N-bromosuccinimide in carbon tetrachloride and in the presence of benzoyl
peroxide produced the relatively unstable bromide 10, which reacted with sodium azide in
dimethylformamide to give the final α-azido ester 11 in an overall yield of 60%.
The azido carboxylates as rhamnofuranose mimetics containing a constituent α-amino
acid moiety at the anomeric position were applied to the generation of a wide range of
rhamnofuranose mimics, including anomeric spiro derivatives such as the rhamnose analogue of the bicyclic herbicide hydantocidin. These compounds were conceived as tools
for elucidating the biosynthesis of the cell walls of mycobacteria [6].
Sugar Amino Acids
HO
HO
O
HO
141
O
THF
HO
formation
O
HO
OH
HO
glucoheptonolactone
HO
OH
OH
1. α-bromination
2. azide displacement
O
O 1 N3
α CO2Me
O
RO
OR
Scheme 7.4 Three-step approach for the generation of epimeric azido esters containing a
glucofuranosyl moiety from glucoheptonolactone
The three-step approach consisting of ring contraction, radical bromination and azide
displacement was also applied for the generation of epimeric azido esters containing a
glucofuranosyl moiety from glucoheptonolactone. In this case, the furanoid species was
generated from a γ-lactone (Scheme 7.4). These protected molecules were further reduced
to the corresponding amino esters, and taken as intermediates for the generation of combinatorial libraries of glucofuranose mimics and of spiro derivatives of glucofuranose at the
anomeric position [7].
The same research group reported other papers on anomeric α-SAAs derived from mannofuranose as building blocks for the incorporation of mannofuranose units into peptide
chains and for the formation of spirodiketopiperazines [8]. In this report, a novel oxidative
ring contraction was conceived, starting with bromination at C2 of the lactone, followed
by azide reduction and ring opening of imino lactone by methanol to give an open-chain
hydroxyimine, which then cyclized to form the epimeric amino esters.
Interesting work on the synthesis of α-SAAs was proposed by Lakhrissi and Chapleur
[9], who reported a two-step route to α-chloro- and α-azido-ulosonic esters from lactones involving the reaction of dichloroolefins with m-chloroperbenzoic acid (mCPBA).
Subsequent substitution of chlorine by the azide ion yielded the corresponding anomeric
α-azido esters (Scheme 7.5). This reaction proceeds with high stereocontrol, likely via
dichloro-epoxide formation followed by fast rearrangement to acyl chloride and esterification. The first step is the formation of a dichloro-epoxide 13 from dichloroolefin 12, which
rearranges quickly to the corresponding chloroacyl chloride 14 and reacts with methanol.
As a consequence of the rearrangement, the chlorine atom is cis to the isopropylidene ring,
and as a result the final α-azido ester 15 has the azide group trans to the isopropylidene,
due to inversion of configuration during azide substitution by treatment of the chloro ester
with sodium azide.
Finally, Fleet et al. reported a multigram synthesis of two epimeric six-carbon THF carboxylates based upon a d-arabinofuranose template, to obtain such building blocks suitable
for the generation of oligomers possessing well-defined secondary structures. Here, the radical bromination was also taken into account for the introduction of the nitrogen species at
C2 to afford anomeric α-amino acid derivatives [10].
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Peptidomimetics in Organic and Medicinal Chemistry
Cl
O
Cl
O
O
O
O
Cl
O
O
mCPBA
O
O Cl
O
12
O
13
1. MeOH
2. NaN3
O 1 N3
O
O
O
O
O
O
15
Scheme 7.5
Cl Cl
O
α CO2Me
O
O
O
14
α-SAA from the reaction of dichloroolefins with m-chloroperbenzoic acid
HO
O 1 NH2
α CO2H
HO
OH
OH
(a)
O
OH
4
H2N α
HO2C
OH
OH
(b)
Figure 7.3 Structure of pyranoid SAA possessing the amino and carboxylic functions at the
anomeric position (a) C1 and (b) at C4
7.2.2
Pyranoid 𝛂-SAAs
Most reported α-SAAs have a furanoid scaffold, and only a few examples of pyranoid
species were developed. Among this group of SAAs, application of the two amino and
carboxylic groups was conceived also at positions other than the anomeric one, as always
found in furanoid scaffolds; an example of an α-SAA possessing such groups at C4
appeared in the literature in 2000 (Figure 7.3).
According to the procedure using thiazolyl ketol acetate species reported for furanoid SAA (Scheme 7.1), with 16 the N-glycosidation of either α- or β-anomer with
TMSN3 -TMSOTf gave stereospecifically the azido galactopyranoside 17 in 88%
isolated yield (Scheme 7.6). The crude aldehyde 18, obtained by application of the
thiazolyl-to-formyl deblocking procedure, was converted into the α-azido ester 19 (54%
yield from 18), which gave the amino ester 20 in 62% yield by selective reduction of the
azido group using Pd-catalysed hydrogenation.
A different approach to pyranoid α-SAAs took advantage of the incorporation of the
anomeric centre of d-mannopyranose [11]. The authors reported the development of
d-mannopyranose derivatives incorporating an anomeric α-amino acid component. The
Sugar Amino Acids
S
S
N
O
BnO
OAc
BnO
143
TMSN3
TMSOTf
88%
OBn
N
O
BnO
N3
BnO
OBn
16
OBn
OBn
1. TfOMe 17
2. NaBH4
O
BnO
3. HgCl2
1 CO2Me 1.Ag2O
α N3
BnO
2.CH2N2
54%
OBn
OBn
OBn
18
19: R = N3
62%
N3
BnO
OBn
H2, Pd/C
CHO
O
BnO
20: R = NH2
Scheme 7.6 Synthetic approach to a pyranoid-based α-amino acid a using thiazolyl ketol
acetate species
OH
OPg
O
PgO
PgO
O
N-bromophthalimide
N Pg
OPg H
21
H2 Pd/C HO
O
PgO
PgO
O
HN
Pg 22
O
O 1
NH
α
O
OPg
HO
OPg
23
Pg=protecting group
Scheme 7.7 Synthesis of D-mannopyranose-derived α-SAA from an acylated bicyclic [2.2.2]
lactone
N-acylated bicyclic [2.2.2] lactone 22, formed via an oxidative ring closure, gave access
to glycopeptide analogues of d-mannopyranose. It was ascertained that mannopyranose
derivatives containing an α-amino acid moiety at the anomeric position are less stable
than the mannofuranose isomers. The synthetic strategy employed the oxidation of the C2
nitrogen-bearing substituent of δ-lactone 21 with concomitant closure from the hydroxy
group at C6 to produce a [2.2.2] bicyclic lactone 22, which upon opening gave the amino
acid derivative 23 with complete anomeric stereocontrol (Scheme 7.7).
A pyranoid SAA from the corresponding hydantoin derivative was prepared by taking
advantage of the carbohydrate precursor 24, which possess the ketone moiety at C4, thus
resulting in a non-anomeric pyranoid α-SAA (Scheme 7.8) [12]. The addition of cyanide
ion, followed by hydantoin formation (26) and hydrolysis of the deprotected hydantoin 27
provided inclusion of the amino and carboxylic functions at the C4 position of the pyranoid
scaffold 28.
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Peptidomimetics in Organic and Medicinal Chemistry
O
OMe
O
KCN
O
O
O
OMe
NC
(NH4)2CO3
O
HO
HN
NH
O
24
O
O
OMe
O
O
O
25
26
H3O+
O
HO2C
OMe
4
H2N
OH
α
OH
OH
28
O
O
OMe
-
HN
NH
O
OH
OH
27
Scheme 7.8 Pyranoid sugar α-amino acid via the corresponding hydantoin derivative to install
the amino and carboxylic functions at C4
7.3
7.3.1
𝛃-SAAs
Furanoid 𝛃-SAAs
Most research in the field of β-SAAs has concentrated on the furanosidic scaffold. In the
group of β-SAAs encompassing both furanosidic and pyranosidic structures, two major
subgroups can be ascribed as a function of the position of the carboxylic and amino functions, one group embracing all the compounds possessing both the amino and carboxylic
groups at C1 of the sugar moiety and the second group consisting of compounds having
the amino group at C2 and the carboxylic group at C1.
To produce inexpensive and chemically diverse carbohydrate building blocks more
amenable for use in combinatorial organic synthesis, amino and carboxylic functional
groups were incorporated into several monosaccharides. In the work by McDevitt and
Lansbury [13], a series of 12 SAAs were prepared from commercially available starting
materials, and oligomeric ‘glycotides’ were generated through conventional solution-phase
peptide synthesis techniques. The synthesis considered the suitably protected furanosidic
species 29 to install the azido group via triflate displacement reaction by sodium azide,
followed by oxidation of the primary alcohol group of 30 to produce the anomeric furanoid
β-SAA 31 (Scheme 7.9).
Fleet and coworkers reported a series of β-SAAs possessing the carboxylic function at the anomeric position. In a first report [14], furanoid β-SAAs derived
from d-glucoheptonolactone were synthesized and applied as building blocks for
β-oligopeptides (Scheme 7.10). Specifically, the β-azido-tetrahydrofuranyl-2-carboxylate
32, as the β-SAA precursor, was derived from the corresponding azido ester 33. This
compound was obtained by introducing the azido group at C4 of the five-membered
ring 34 with inversion of configuration, thus obtaining a building block with the
d-glycero-d-allo-heptonate stereochemistry. The key step in the synthesis of the furanoid
C-glycoside 34 involved the treatment of a 2-O-triflate of a carbohydrate lactone with
acidic methanol, followed by hydrolysis of the side-chain acetonide and methanolysis of
Sugar Amino Acids
HO
O
O
O
HO
O
2. CH3I
O
MeO2C
3. TBAF
O
β
O
N3
O
29
1. KMnO4
O
2. NaN3
O
HO
HO
1. Tf2O
OTBDPS
O
TBDPS-Cl
py
145
O
N3
31
30
Scheme 7.9 Furanoid β-SAA obtained by installing the azido group via a triflate displacement
reaction, and the carboxylate function through oxidation of the primary hydroxyl group
O
O
HO2C
O
O
CO2Me
OR
β
N3
N3
OTBDMS
32
OTBDMS
33
HO
HO
HO
O
HO
HO
35
O
OH
O
HO
HO
CO2Me
OH
34
Scheme 7.10 Furanoid β-SAA derived from D-glucoheptonolactone
the lactone, with concomitant intramolecular displacement of the triflate at C2 of 35 by
the hydroxyl group at C5.
In another report [15], an anomeric β-SAA was obtained by azide insertion to the suitably
protected furanosidic hexose 36, followed by deprotection via hydrolysis to achieve a free
azido hexopyranose 37 as the substrate for the formation of γ-lactone 38 through bromine
oxidation. After selective protection of C5 and C6 hydroxyls as acetonide, the target β-azido
ester 39 was obtained by esterification of the remaining free hydroxyl group in 38 with
triflic anhydride, followed by reaction with hydrogen chloride in methanol (Scheme 7.11).
A similar approach (Scheme 7.12) was applied for the straightforward synthesis of the
furanoid β-SAA 3-amino-3-deoxy-1,2-isopropylidene-α-d-ribofuranoic acid 44 starting
from diacetone glucose 40. This building block was also applied in the synthesis and
NMR conformational analysis of linear and cyclic oligomers as structural templates for
peptidomimetic drug design [16]. After insertion of the azido group at C3 of 41, the
desired anomeric β-SAA was obtained by deprotection and oxidative demolition of the
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Peptidomimetics in Organic and Medicinal Chemistry
OH
O
O
O
O
O
OH 1. Br2, BaCO3
aq. TFA
2. acetone, CSA
HO
OH
O
N3
N3
36
37
O
O
O
N3
O
HO
1.Tf2O, py
O
2.HCl-MeOH
CO2Me
β
OH
HO
38
N3
39
Scheme 7.11 Synthesis of anomeric β-SAA via the formation of a γ-lactone intermediate
through bromine oxidation
1. Tf2O,py
O
O
O
O
2. NaN3
O
O
O
O
HO
41
O
O
N3
42
Scheme 7.12
glucose 40
1.H2,Pd/C
1. NaIO4
2. KMnO4 HO2C
O
HO
HO
AcOH
O
N3
40
O
O
O
O
N3
43
O
2.Fmoc-Cl HO2C
O
β
Fmoc
NH
O
44
Synthesis of the α-D-ribofuranoic acid-based furanoid β-SAA 44 from diacetone
hydroxyl groups at C5 and C6 of 42, followed by final oxidation of the primary alcohol to
the corresponding carboxylic acid 43. The β-SAA was then obtained as a Fmoc-derivative
after azide reduction by catalytic hydrogenolysis and amine protection.
Access to another furanoid β-azido ester (Scheme 7.13) was achieved from l-arabinose
45 through conversion of this hexose into the corresponding δ-lactone 46, and activated as
2-O-triflate, followed by ring contraction and subsequent manipulation of 47 to introduce
the azide via the 3-O-triflate [17].
Finally, entry to a furanoid β-SAA possessing the carboxylic group at C2 and the amino
surrogate at the anomeric position was achieved by formal homologation of the anomeric
α-SAA species [18]. Specifically, the synthesis of fused furanosyl β-amino esters from
protected sugar lactones was accomplished by combining a Wittig-type reaction and the
1,4-addition of benzylamine on the resulting glycosylidenes (Scheme 7.14). This sequence
of reactions afforded either N-glycosyl-3-ulosonic acid esters, which are the β-analogues
of anomeric sugar β-amino esters. This series of glycosyl β-amino acids are characterized
Sugar Amino Acids
O
OH
O
O
K2CO3
MeOH
ox
OH
O
O
Tf2O
147
OTf
O
O
py
46
45
1. Tf2O
O
CO2Pr
OH
TBDPSO
O
CO2Pr
2. NaN3
β
TBDPSO
N3
47
48
Scheme 7.13 Access to a furanoid β-azido ester (48) from L-arabinose through ring contraction of the δ-lactone to the tetrahydrofuran ring
R1
O
O
R2
O
Wittigtype reaction
(Z or E)
R1
O
CHCO2Me
R2
O
O
O
R1=H, OMe R2=CH3, OMe
R1=R2=OC(CH3)2OCH2
amine 1,4 addition
R1
NHR
O β
CO2Me
R2
O
O
Scheme 7.14 Formal homologation of anomeric α-SAA species to give the corresponding
furanoid β-SAA
by having the amino group directly linked to the anomeric centre, whereas the carboxylic
group is spaced from C1 by a methylene unit. Such structures can also be regarded as
β,β-disubstituted β-amino acids, which are obtained by a two-carbon chain elongation of
the sugar skeleton from protected aldonolactones using a Wittig-type methodology.
7.3.2
Pyranoid 𝛃-SAAs
A glucose-derived pyranoid β-SAA was synthesized and applied in the bioconjugation to a
peptide possessing an isosteric replacement of the N-glycosidic linkage through a reversed
amide bond [19]. This β-SAA was synthesized by treating the chloro precursor with tributyltin lithium, followed by the generation of the glycosyl dianion 49 and subsequent trapping by carbon dioxide to give β-SAA 50. This building block was also applied in a series
of bioconjugation reactions with suitable amino acid moieties to give C-glycopeptides 51
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Peptidomimetics in Organic and Medicinal Chemistry
BnO
O
BnO
OBn
BnO
O
OH
1. SOCl2 BnO
2. Bu3SnLi
BnO
NHAc
74%
NHAc
83%
NAc
BnO
O
BnO
CO2
CO2H
β
NHAc
BnO
OBn Li
1.BuLi, -78°C
2.BuLi, -55°C
OBn
Li
O
SnBu3
OBn
50
peptide coupling
49
O
BnO
O
N
H
β NHAc
BnO
n
O
HN
OBn
51
Scheme 7.15
β-SAA
Synthesis and peptide bioconjugation strategy of a glucose-derived pyranoid
possessing an inverted amide linkage with respect to glucopyranosyl-asparagine derivatives
(Scheme 7.15).
Kessler and coworkers reported an important work on the synthesis of various SAAs, and
their application to linear and cyclic peptides, also providing detailed conformational analysis of the peptidic constructs. In this work, a glucosamine-derived β-SAA was conceived
as a γ-turn mimetic [20]. Starting from d-glucosamine, the partially benzylated sugar 52
was protected at the amino function as Cbz in 90% yield (Scheme 7.16). Then, chlorination of the anomeric hydroxyl group provided the chloro compound, which was treated
with tributyltin lithium to afford 53 in 79% yield. The glycosyl dianion 54 was generated
in two steps by modulating the temperature: first, deprotonation of the urethane nitrogen
occurred at −78 ∘ C using 1 equiv. of BuLi, and then transmetalation at −55 ∘ C was achieved
using 1.2 equiv. of BuLi. The dianion 54 was subsequently trapped by carbon dioxide to
afford the Cbz-protected β-SAA 55 (83% yield) possessing the carboxylic function at the
anomeric position.
7.4
𝛄-SAAs1
Fleet reported the generation of THF-templated γ-amino acids starting from sugar-derived
lactones (Scheme 7.17) [22]. The 2-triflate of carbohydrate δ-lactones 56 when treated
1 Trabocchi et al. [21]. Reproduced by permission of John Wiley and Sons, Copyright (c) 2009 John Wiley and Sons.
Sugar Amino Acids
149
1.Cbz-Cl
OBn
SnBu3 1. 1 eq.BuLi, -78°C
2. 1.2 eq. BuLi, -55°C
Cbz
N
OBn H
52
53
O
BnO
OH
2.SOCl2
O
BnO
3.Bu3SnLi
BnO
BnO
NH3+Cl-
O
BnO
Li
CO2
N Cbz
BnO
O 1 CO2H
BnO
β
BnO
γ-turn
NH
OBn Li
OBn Cbz
54
55
Synthesis of a glucosamine-derived β-SAA and application as a γ-turn mimetic
Scheme 7.16
R1O
OH
R2O
O
a
O
57
OR1
XO
R1O
OH
R2O
O
O
56
O
OR1
TfO
O
N3
γ NH
O
O
b
R1O
N3
O
59
THF templated
γ-peptides
O
58
X = Tf or protecting group
R1 = protecting group
Scheme 7.17
THF-templated γ-amino acids starting from sugar-derived lactones
with methanol in the presence of either an acid or base catalyst underwent efficient ring
contraction to highly substituted THF-2-carboxylates 57. Initial nucleophilic opening of
the lactone ring by methanol, followed by subsequent SN 2-type ring closure of an intermediate hydroxy triflate forms the THF ring, with inversion of configuration at the C2
position. Thus, synthesis of the THF γ-azido esters (59) using this strategy allowed for the
introduction of the C4 azido group either after (route a) or before (route b) formation of
the THF ring.
Access to bicyclic furanoid γ-SAA was reported by Kessler et al. starting from diacetone
glucose (60), and the application to solid-phase synthesis for the generation of oligomers
150
Peptidomimetics in Organic and Medicinal Chemistry
O
O
O
O
O
NaN3
O
O
O
RO
O
N3
62
60: R = H
61: R = Tf
Tf2O
O
AcOH
HO
O
HO2C
γ
O
HN
Fmoc
65
O
TEMPO
NaClO HO
HO
O
R
O
O
1. H2,Pd/C
63: R = N3
2. Fmoc-Cl
64: R = NHFmoc
Scheme 7.18 Synthesis of a furanoid γ-SAA from diacetone glucose
was also disclosed [16]. Specifically, azidolysis of the triflate derivative of the diacetone
glucose 61 gave the intermediate 62, which, after deprotection of exocyclic hydroxyl
groups, was subjected to azide conversion into Fmoc-protected amine 64 in a one-pot
process. Final oxidation of the primary hydroxyl group furnished the corresponding
furanoid α-hydroxy-γ-amino acid 65 (Scheme 7.18).
The first effective solid-phase chemical method for the preparation of carbohydrate-based
universal pharmacophore mapping libraries was reported by Sofia et al. [23] The sugar
scaffold 70 has three sites of diversification, with an amino and a carboxylic group of
the γ-amino acid scaffold, and an additional hydroxyl group. The synthesis started from
d-glucose derivative 66 (Scheme 7.19), which was treated with NaIO4 and nitromethane
to introduce a nitro group at C3. Subsequent orthogonal protections and conversion
of the nitro group into the corresponding protected-amino group, gave 69, which was
further oxidized to the γ-amino acid 70 by the TEMPO–NaClO system (TEMPO =
2,2,6,6-tetramethylpiperidine-1-oxyl). By anchoring the carboxylic group on a solid
phase, libraries of 1648 members were prepared using eight amino acids as acylating
agents of the amino group and six isocyanates for functionalization of the hydroxyl group.
7.5
7.5.1
𝛅-SAAs2
Furanoid 𝛅-SAAs
Among furanoid δ-SAAs, monocyclic compounds or oxabicyclo[3.3.0]octane and oxabicyclo[3.2.0]heptane structures have been synthesized by several authors according to different synthetic routes (Figure 7.4).
2 Trabocchi et al. [21]. . Reproduced by permission of John Wiley and Sons, Copyright (c) 2009 John Wiley and Sons.
Sugar Amino Acids
O
HO
OMe
1.NaIO4
HO
O
HO
2.NaOMe,MeNO2
OMe
HO
OH
OH
OH
NO2
66
67
1.PhCH(OMe)2,H+
2.Ac2O,py
O
O
Ph
OMe
O
151
1.H2,Pd(OH)2/C
2.Fmoc-O-Su
OAc
NO2
68
O
HO
HO
HN
OMe
HO2C
TEMPO,NaClO
O
OMe
OAc
HO
γ
HN
OAc
Fmoc
Fmoc
70
69
Scheme 7.19 Development of a pyranoid γ-SAA possessing three sites of diversification for
the production of chemical libraries
O
monocyclic
OR'
O
O
O
H2N
O
O
H2N
O
Figure 7.4
SR
HO2C
CO2H
OH
O
H2N
RO
CO2H
H2N
O
[3.2.0]
CO2H
H2N
RO
[3.3.0]
O
CO2H
H2N
O
O
HO2C
NH2
O
OH
Classification of furanoid δ-SAA structures
CO2H
152
Peptidomimetics in Organic and Medicinal Chemistry
Furanoid δ-SAAs 73 and 76 have been obtained using different strategic approaches by
three different authors: Le Merrer, Chakraborty and Fleet. Le Merrer used mannose as the
starting material to generate the enantiomerically pure double epoxide 71 [24], which was
treated with NaN3 and silica gel to give the corresponding azidomethyl-furanoid sugar 72.
Oxidation of the primary hydroxyl group and conversion of the azide into Boc-protected
amine produced the corresponding furanoid δ-SAA 73. Starting from the enantiomeric
epoxide 74, also obtained from d-mannitol in six steps, it was possible to achieve the
δ-amino acid 76 having the same orientation of functional groups relative to the ring,
but inverted configurations of the amino and carboxylic functions at C1 and C5 positions,
respectively (Scheme 7.20).
Chakraborty’s approach consists of an intramolecular 5-exo ring-opening of a terminal N-Boc-aziridine [25], derived from α-glucopyranose, during alcohol to acid oxidation,
resulting in the protected furanoid δ-SAA 82 similar to 73 and with complete stereocontrol (Scheme 7.21). The stereoisomeric aziridine obtained with the same treatment from
d-mannose precursor generated the corresponding isomeric δ-amino acid 83, having the
configuration at C1 inverted.
Fleet et al. reported a range of stereoisomeric furanoid δ-SAAs starting from
sugar-derived lactones [26]. For example, the previously described compound 82
was obtained as azido ester 87 from d-mannono-γ-lactone 84 by acid-catalysed ring
rearrangement of the corresponding triflate derivative 85 (Scheme 7.22).
More recently, the same authors reported the synthesis of all diastereomeric precursors
to THF-templated δ-amino acids lacking the hydroxyl at C2, starting from mannono- and
gulono-lactones [27], in analogy with the corresponding THF-templated γ-amino acids
(Scheme 7.23). Two different strategic approaches have been proposed, by changing the
order of deoxygenation and THF formation reactions.
The hydroxylated THF-carboxylic acid derivatives were further manipulated to obtain
the azido esters as δ-amino acid precursors: selective activation of the primary hydroxyl
group with tosyl chloride was followed by azide insertion at the δ-position.
O
4 steps
D-Mannitol
NaN3
BnO
OBn
O
O
HO
N3
BnO
OBn
O-
O
BnO
N3
1.Na2Cr2O7, then CH2N2
71
six steps
2.H2,Pd/C
MeO2C
1.Na2Cr2O7, then CH2N2
O
NaN3
BnO
OBn
O
HO
N3
BnO
O
74
Scheme 7.20
epoxides
OBn
75
OBn
72
2.H2,Pd/C
3.Boc2O MeO2C
O
3.Boc2O
δ
O
NHBoc
BnO
δ
OBn
73
NHBoc
BnO
OBn
76
Furanoid δ-SAA obtained from mannose through enantiomerically pure double
Sugar Amino Acids
N3
BnO
O
OMe
HCl
O
N3
OBn
OH
OH
NaBH4
OBn
α-glucopyranose
derivative
77
OBn
N3
OH
OBn MeOH
BnO
153
OBn OBn
OBn
79
78
Ph3P
BocHN
O
δ
CO2H
R
N
PDC,DMF
OBn
OH
HO
OH
OBn OBn
82
80: R = H
81 R = Boc
Boc2O
BocHN
O
δ
D-mannose derivative
HO
CO2H
OH
83
Scheme 7.21 Synthesis of furanoid δ-SAA by intramolecular 5-exo ring-opening of a terminal
N-Boc-aziridine
HO
OH
TfO
O
O
Tf2O
O
OH
O
O
O
O
D-mannono-γ-lactone
84
O
85
HCl
MeOH
δ
O
N3
HO
OH
87
Scheme 7.22
CO2Me
1. TsCl
2. NaN3
O
HO
HO
CO2Me
OH
86
Synthesis of furanoid δ-SAA from D-mannono-γ-lactone
Quite recently, a set of conformationally locked δ-amino acids have been proposed, based
on furan rings [28]. In particular, a bicyclic furano-oxetane core has been proposed as scaffold for a constrained δ-amino acid. The synthetic strategy was based upon CO-insertion
on fully protected β-d-ribofuranoside 88, followed by conversion of the primary alcohol
function at C1 into azide to give 90. After hydroxyl group protection/deprotection steps,
oxidation of the primary alcohol group, followed by aldol condensation with formaldehyde
154
Peptidomimetics in Organic and Medicinal Chemistry
HO
deoxygenation
HO
O
O
O
O
O
OH
O
THF formation
OH
O
MeO2C
O
OH
O
HO
OH
deoxygenation
THF formation
MeO2C
O
OH
Scheme 7.23 Synthesis of THF-templated δ-amino acids using different approaches by
changing the order of deoxygenation and THF formation reactions
and oxetane cyclization produced 97, which was treated with Boc-on and Me3 P to convert
the azido group into the corresponding Boc-protected δ-amino acid 99 (Scheme 7.24).
Inversion of functional groups to obtain the isomeric δ-amino acid 106 was accomplished
by protection of the alcohol function at C1 of 100 as the TBDPS (tert-butyldiphenylsilyl)
ether, followed by conversion into Boc-protected amino group of the newly generated
hydroxyl function at C5 via azide formation (Scheme 7.25).
The conformational rigidity of pyran and furan rings makes carbohydrate-derived
amino acids interesting building blocks in the introduction of specific secondary structures in peptides. For example, compound 109 (Scheme 7.26) was incorporated into
the cyclic peptide containing the RGD loop sequence by SPPS (solid-phase peptide
synthesis) using Fmoc chemistry [29]. Reduction of the azide to an amine group and
coupling with the desired amino acid was realized in one-pot in the presence of Bu3 P
and carboxylic acid activating agents. Allyl compound 107, derived from allylation of
2,3,5-tri-O-benzyl-d-arabinofuranose, underwent iodocyclization to 108 as a diastereomeric mixture that was easily separated by chromatography. This step, which is crucial
for the formation of bicyclic scaffolds, consisted of an intermediate iodonium ion opening
by attack of the γ-benzyloxy group, and formation of a cyclic iodo-ether with simultaneous
debenzylation. The final azido acid 109 was obtained by reaction with Bu4 NN3 , followed
by selective deprotection steps and primary alcohol Jones’ oxidation.
7.5.2
Pyranoid 𝛅-SAAs
δ-Amino acids belonging to the SAA class constrain a linear peptide chain when the NH2
and COOH groups are in 1,4 positions. In particular, such δ-SAAs have been thought as
a rigidified d-Ser-d-Ser dipeptide isosteres (Scheme 7.27) [20]. Synthesis of the β-anomer
was reported starting from glucosamine.
Ichikawa et al. reported the synthesis of a series of glycamino acids and their incorporation in oligomeric structures, a family of SAAs that possesses a carboxylic group at
C1 position and the amino group at C2, -3, -4 or -6 position [30]. In particular, δ-amino
acids with the amino group at C4 or C6 were reported; the syntheses are shown in
Sugar Amino Acids
O
O
OAc
CO
BzO
BzO
BzO
Co2(CO)8
OBz
OH
BzO
1. MsCl
2. NaN3
O
BzO
OBz
88
N3
RO
t-BuOK
MeOH
89
155
OR
90: R = Bz
91: R = H
2,2-dimethoxypropane
H
O
RO
N3
RO
O
O
1. CH2O
2. NaBH4
O
N3
O
O
O
HO
N3
O
O
O
92
93
94: R = OH
95: R = OMs
MsCl
Dess-Martin
periodinane
HCl
O
MsO
N3
MsO
HO
N3
1. Boc-on, Me3P
O
RO
NaOH
96
δ
O
N Boc
H
2. TEMPO, NaClO
O
OH
HO2C
OH
O
OH
97: R = Ms
98: R = H
HCl
99
Scheme 7.24 Synthesis of a constrained δ-amino acid containing a bicyclic furano-oxetane
from β-D-ribofuranoside
OH
BzO
1. Dess-Martin
RO
OTBDPS 2. CH2O
RO
3. NaBH4
O
O
BzO
1. TBDPS-Cl
HO
2. t-BuOK, MeOH
OBz
3.
O
MeO OMe
100
O
O
OTBDPS
O
101
O
102: R = H
103: R = Ms
MsCl
1. FeCl3
2. NaOH
δ
BocHN
1. NaN3
O
O
CO2H
OH
106
TEMPO
NaClO
O
BocHN
2. Boc-on
OH
O
OH
105
O
MsO
OTBDPS
3. TBAF
OH
O
104
Scheme 7.25 Synthesis of constrained δ-amino acid 106 from β-D-ribofuranoside with
inversion of the functional groups position with respect to 99
156
Peptidomimetics in Organic and Medicinal Chemistry
H
O
I2
BnO
I
O
O
BnO
BnO
OBn
H
BnO
108
107
1.Bu4NN3
H
N3
O
2.Ac2O
HO2C
3.MeONa
O
4.Jones
H
BnO
109
Scheme 7.26 Synthesis of bicyclic SAA precursor 109 by allylation of 2,3,5-tri-O-benzylD-arabinofuranose and subsequent iodocyclization
HO
HO
OH
OH
O
H2N
HN
H3CO
O
Sugar δ-aa
D-Ser-D-Ser
OH
CO2H
O
NH
OAc
O
OH
NH3+Cl-
Br
O
AcBr
HO
OAc
NH3+Br-
AcO
OH
D-glucosamine
1. MeOH,Py
2.Cbz-Cl
O
OMe
AcO
OAc
110
NHCbz
OAc
111
MeOH
Me2EtN
OH
HO2C
O
OMe
δ
HO
NHCbz
OH
113
Scheme 7.27
isostere
O
Pt/C
O2
HO
OMe
NHCbz
OH
112
Development of a pyranoid δ-amino acid from D-glucosamine as a D-Ser-D-Ser
Sugar Amino Acids
O
HO
CO2Me
HO
OH
O
O
PhCHO
Ph
157
CO2Me
O
OH
OH
OH
114
115
1. NaH, BnBr
2. NaBH3CN, HCl
3. Tf2O
4. NaN3
O
HO
Boc
CO2H
δ
N
H
OH
BnO
1. H2, Pd(OH)2/C
R
2. LiOH, MeOH
O
CO2Me
OBn
OBn
OH
118
1. H2S
116: R = N3
2. Boc2O
117: R = NHBoc
Scheme 7.28 δ-Amino acid monomer for β-1,4-linked oligomers
O
HO
HO
OH
CH3NO2
HO
O
NO2
HO
OH
OH
OH
OH
D-glucose
119
1. H2, Pd/C
2. Fmoc-Cl
HO2C
O
HO
δ
N
H
OH
OH
Fmoc
TEMPO
NaClO HO
O
HO
N
H
Fmoc
OH
OH
120
Scheme 7.29 Synthesis of pyranoid δ-amino acid 120 from glucose using a nucleophilic aldol
reaction to introduce a nitromethylene group at the anomeric position
Schemes 7.28 and 7.29. Benzylidene-protected ester 115 was obtained starting from
methyl β-d-galactopyranosyl-C-carboxylate 114 by treatment with benzaldehyde and
formic acid. O-Benzylation and reductive opening of the benzylidene group were followed
by treatment with Tf2 O and NaN3 to give the Boc-protected amino group at C4 of 117.
Oligomerization was carried out using deprotected hydroxyl functions of Boc-protected
δ-amino acid 118.
The δ-amino acid 120 was synthesized starting from d-glucose, and using a nucleophilic
aldol reaction to introduce a nitromethylene group at the anomeric position of 119 as an
158
Peptidomimetics in Organic and Medicinal Chemistry
aminomethylene equivalent, followed by selective oxidation of the primary hydroxyl group
to a carboxylic acid (Scheme 7.29) [31].
As an alternative approach to pyranosidic glucose-derived δ-amino acids, Xie proposed a
synthetic route from β-C-1-vinyl glucose to generate δ-SAAs (Scheme 7.30) [32]. Starting
from vinyl-glucoside 121, selective deprotection of the 6-benzyloxy group afforded 122.
Primary alcohol oxidation with pyridinium chlorochromate (PCC) led to 126, which was
treated with O3 /NaBH4 as an oxidation–reduction step to insert a hydroxymethyl function at C1. Final activation and azide insertion produced the δ-amino acid precursor 128.
Alternatively, azide insertion at C6 via mesylation of the hydroxymethyl group followed
by treatment with NaN3 allowed the synthesis of the δ-amino acid precursor 125, thus
inverting the order of reactions. Oligomerization was carried out in solution using the corresponding azido ester and protected amino acid for subsequent coupling reactions.
The synthesis of a pyranoid δ-amino acid has also been described by Sofia for the
solid-phase generation of carbohydrate-based universal pharmacophore mapping libraries
[23]. The sugar scaffold was provided with three sites of diversification, using an amino
and a carboxylic group of the δ-amino acid scaffold, and an additional hydroxyl group. The
selected δ-amino acid scaffolds were synthesized from glucosamine by amine protection as
Cbz-urethane, followed by treatment with 2,2-dimethoxypropane to protect the hydroxyl
groups at C5 and C6. Methylation of hydroxyl at C4 afforded the orthogonally protected
130. Subsequent hydrogenation, Fmoc-protection and oxidation with the TEMPO–NaClO
system gave the δ-amino acid 132 with a free hydroxyl function at C4 (Scheme 7.31).
1.TMSOTf, Ac2O
O
BnO
2.NaOMe,MeOH
BnO
OBn
HO
BnO
OBn
121
1.O3
OH 2.NaBH4
BnO
OBn
N3
N3
O
BnO
OBn
OBn
126
1.MsCl
1.O3
2.NaN3
2.NaBH4
O
BnO
RO2C
OBn
O
OH
BnO
OBn
123
OBn
124
δ
OBn
OBn
122
O
N3
PCC, Ac2O RO2C
ROH
O
OBn
OBn
127
PCC, Ac2O
1.MsCl
ROH
2.NaN3
δ
O
BnO
CO2R
OBn
OBn
125
RO2C
O
BnO
N3
OBn
OBn
128
Scheme 7.30 Synthetic routes from β-C-1-vinyl glucose to pyranoid δ-SAAs
Sugar Amino Acids
O
HO
OH
NH3+Cl-
HO
1.Cbz-Cl
2.MeOH,HCl
O
HO
OH
O
O
O
OCH3
130
HO2C
O
HO
OCH3
131
OCH3
N
H
N
H
Cbz
129
MeO OMe
1.
2.NaH,CH3I
OCH3
HO
OH
D-glucosamine
159
Cbz
OCH3
N
H
1.H2,Pd/C
2.Fmoc-Cl
Cbz
1.p-TsOH
2.TEMPO,NaClO
HO2C
O
OCH3
δ
HO
OCH3
N
H
Fmoc
132
Scheme 7.31 Arrows indicate the points of diversity
7.6
Representative Applications in Medicinal Chemistry
Early reports on the application of SAAs were given by Kessler between 1994 and 1996
[20, 31], who first described the use of SAAs to make analogues of Leu-enkephalin and
somatostatin, taking advantage of their ability to constrain linear backbone conformations
or distinct turn structures. The specific propensity of furanoid SAAs with respect to pyranoid ones, when inserted in a peptide fragment, to establish intramolecular hydrogen-bonds
between its hydroxyls and the main chain amides from their pyranoid counterparts was
assessed. This was demonstrated by inserting a glucose-derived furanoid δ-SAA as a dipeptide isostere of the Gly-Gly sequence of Leu-enkephalin to give an analogue 133 consisting
of Tyr-SAA-Phe-Leu, which possesses high similarity to the bioactive conformation of
Leu-enkephalin (Figure 7.5).
A detailed structural analysis of several peptidomimetic molecules containing furanoid
SAA scaffolds showed that the free hydroxyl groups on the sugar rings prevent short linear
hybrid peptides containing this type of SAA from adopting regular β-turn structures, as
these hydroxyl groups themselves act as hydrogen-bond acceptors with adjacent hydroxyls,
and in most cases they act as both hydrogen-bond donor and acceptor in the same molecule
[33]. In SAAs, unlike in serine and threonine, the hydroxyls are conformationally restricted,
forcing them to participate in the formation of unusual secondary structures. The unique
behaviour of furanoid SAAs in experiencing intramolecular hydrogen-bonds when inserted
in peptide fragments was also reported by Overhand et al. [34], who described that in the
X-ray structure gramicidin S analogue 134, containing a furanoid SAA as a β-turn surrogate
(Figure 7.6), an intramolecular hydrogen-bond between a hydroxyl group at C3 and the
amide proton belonging to the sugar ring contributed to the stabilization of a well-defined
reverse-turn structure.
160
Peptidomimetics in Organic and Medicinal Chemistry
O
O
Boc
O
H
N
N
H
N
H
HO
133
HO
H N
O
H
CO2Me
9-membered
intramolecular
hydrogen-bond
Leu-enkephalin Tyr-Gly-Gly-Phe-Leu
peptidomimetic
Figure 7.5
O
Tyr---SAA---Phe-Leu
Leu-enkephalin peptidomimetic containing a furanoid δ-SAA
HO
3
O
O
OH
O
N H
HN
N H
O
134
Figure 7.6
Gramicidin S peptidomimetic containing a furanoid δ-SAA
O
T
K
O
O
w
Y
NH
O
Figure 7.7 Cyclopeptidic somatostatin analogue containing a furanoid β-SAA: T = Thr,
K = Lys, w = D-Trp and Y = Tyr
Another entry to the application of these cyclic sugar-derived amino acids consisted of
the generation of somatostatin analogues containing a SAA [35] (Figure 7.7) possessing
antiproliferative and apoptotic activity against both multidrug-resistant and drug-sensitive
hepatic carcinoma cells. Four analogues showed IC50 values in the low micromolar range,
making them promising leads for chemotherapeutic drugs against multidrug-resistant carcinoma.
An important field of application of SAAs is represented by oligomeric species
containing multiple copies of a SAA, with the aim of addressing extended molecular
Sugar Amino Acids
HO
HO
HO
N
H
HO
O HO
N
H
O
HO
HO
O HO
HO
Boc
HO
HO
4
O HO
N
H
O
O
N
H
O
3
161
NH
R
O
2
1
Tetrameric structure consisting of β-(1-2)-type glycamino acids
Figure 7.8
interactions such as protein–protein interactions and oligosaccharide recognition events.
Ichikawa reported the generation of O-sulfated glycamino acid oligomers [30], which
were able to inhibit the replication of HIV-1 (human immunodeficiency virus) and sialyl
Lewis x-dependent cell adhesion. Conformational analysis by 2D NMR revealed that the
β (1-2)-trimer and tetramer species (Figure 7.8) tend to assume a 14-helical conformation
in solution, and this folding preference was assumed as a consequence of the β-amino acid
moiety embedded in the β-(1-2)-type glycamino acid.
An entry to branched oligomeric species containing alternating β- and δ-SAA was
reported by Sicherl and Wittmann [36], which specifically synthesized glycamino
oligomers using protected derivatives of 2,6-diamino-2,6-dideoxy-β-δ-glucopyranosyl
carboxylic acid, and taking advantage of the azide installed at C6 after selective tosylation
of the CH2 OH starting from the deacetylated sugar moiety (Figure 7.9).
Fmoc
δ
N
H
PgO
O
CO2H
O
N3
β NH Boc
β NH Fmoc
PgO
OPg
OPg
H2N
O
O
O
O
δ
PgO
PgO
CO2H
NH2
N
H
PgO
O
Bn
N
H
NH2
N
HO
β
OPg
OPg
N
H
O
OPg
NH2
Figure 7.9
Generation of branched oligomeric species containing alternating β- and δ-SAA
162
Peptidomimetics in Organic and Medicinal Chemistry
7.7
Conclusions
In summary, during the last two decades many efforts have been devoted towards the generation of furanoid and pyranoid SAAs, taking advantage of carbohydrate chemistry and
of significant advances in the construction and arrangement of such building blocks. The
basic strategy consists of installation of the amino acid moiety within the sugar framework, taking advantage of azido and ester groups as key precursors for the amino and
carboxylic species, respectively. SAAs represent an important class of building blocks for
the generation of peptide scaffolds and constrained peptidomimetics, owing to the presence
of a relatively rigid furanoid or pyranoid ring decorated with space-oriented substituents.
Accordingly, important entries in the applications of these chemotypes have been reported
by presenting peptidomimetic constructs, as well as oligomeric species and SAA-peptide
hybrids.
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