N-Alkylated C-Glycosyl Amino Acid Derivatives: Synthesis by a One-Pot Four-Component Ugi Reaction

Article abstract of DOI:10.1002/cplu.202000177

C-glycosides represent an important group of naturally occurring glycosylation derivatives but are also efficient mimetics of native O-glycosides. Here, a one-pot four-component methodology is described toward a library of N-alkylated C-glycosyl amino acid derivatives comprising seven different isopropylidene-protected carbohydrate units. The applied methodology tolerates different amines and isocyanides and provides access to Ugi products in yields up to 85 %. X-ray analysis of selected products bearing three different carbohydrate motifs and comparison of their crystal structures with similar ones deposited in Cambridge Crystallographic Database revealed that four structures adopt different conformations, mostly not typical for peptide structures. This property opens the possibility to exploit here described N-alkylated C-glycosyl amino acid derivatives as templates to access different biotic and abiotic secondary structures.

Full text of DOI:10.1002/cplu.202000177

A Multidisciplinary Journal Centering on Chemistry
Accepted Article
Title: N-Alkylated C-Glycosyl Amino Acid Derivatives: Synthesis by a
One-Pot Four-Component Ugi Reaction
Authors: Kristina Vlahovicek-Kahlina, Zoran Stefanic, Katarina Vazdar,
and Ivanka Jeric
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: ChemPlusChem 10.1002/cplu.202000177
Link to VoR: https://doi.org/10.1002/cplu.202000177
01/2020

10.1002/cplu.202000177
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N-Alkylated C-Glycosyl Amino Acid Derivatives: Synthesis by a
One-Pot Four-Component Ugi Reaction
Kristina Vlahoviček-Kahlina[a],#, Zoran Štefanić[b], Katarina Vazdar[a], and Ivanka Jerić[a],*
Abstract: C-glycosides represent an important group of naturally
development process. To cope with diversity in structure of the
naturally occurring C-glycosides and O-glycosides, a variety of
methods have been developed for the synthesis of C-
glycosides.[6] The majority of them rely on the direct formation of
glycosidic C-C linkages with carbohydrate building blocks as the
“donor” precursors. In addition, intramolecular rearrangements
leading to C-glycosylation or construction of carbohydrate rings
after the installation of the glycosidic C-C bonds were used for the
synthesis of this important group of compounds.
occurring glycosylation derivatives but also efficient mimetics of native
O-glycosides. We describe here
a
one-pot four-component
methodology toward a library of N-alkylated C-glycosyl amino acid
derivatives comprising seven different isopropylidene-protected
carbohydrate units. The applied methodology tolerates different
amines and isocyanides and provides access to Ugi products in yields
up to 85 %. X-ray analysis of selected products bearing three different
carbohydrate motifs and comparison of their crystal structures with
similar ones deposited in Cambridge Crystallographic Database
revealed that four structures adopt different conformations, mostly not
typical for peptide structures. This property opens the possibility to
exploit here described N-alkylated C-glycosyl amino acid derivatives
as templates for accessing different biotic and abiotic secondary
structures.
Introduction
Glycosylation is the most ubiquitous posttranslational modification
of proteins, responsible for diversity in structure and function of
glycoproteins, like modulation of membrane receptor signalling,
transmembrane receptor function, protection from proteases and
immune response, anti-adhesive action, nutrient storage,
epigenetic histone modification and many others.[1] Although N-
and O-glycosides represent the majority of naturally occurring
glycosylation derivatives, C-glycosides also occupy an important
part of the natural product pool with significant biological
activities.[2] Some examples include neodysiherbaine A, an amino
acid isolated from the Dysidea herbacea Micronesian sponge, a
highly selective agonist for the kainate glutamate receptors,[3]
chaufurosides A and B, C-glycosyl flavones isolated from oolong
tea leaves, with anti-inflammatory and chemopreventive
activities,[4] and (+)-varitriol, isolated from a marine-derived strain
of the fungus Emericella varicolo showing strong cytotoxicity
against renal, breast, and central nervous system cancer cell lines
(Scheme 1).[5] Compared to O-glycosylation counterparts, C-
glycosides are resistant toward hydrolytic enzymes and therefore
traditionally selected as mimics of native O-glycosides in drug
Scheme 1. Some examples of naturally occurring C-glycosides.
Multicomponent reactions (MCRs) have also been widely
used for the formation of C-C bond between a carbohydrate
molecule and an aromatic or aliphatic aglycon.[7] Actually,
carbohydrate-based MCRs are considered to be one of the most
versatile methods for the preparation of compound libraries.[8,9]
Among others, these include synthesis of modified nucleosides
with antiviral, antitumor and antibacterial activities,[9]
depsipeptides bearing carbohydrate moieties,[10] or N-glycosyl
conjugates.[11] Dondoni exploited versatile reactivity of
carbohydrate-related compounds to gain new classes of chiral
molecules of biological relevance; C-nucleosides by asymmetric
Biginelli and Hantzsch three-component reactions (3CRs), C-
glycosyl -amino esters by Mannich and Reformatsky reactions,
glycosyl -lactams and heterocyclic -amino acids,[9] and
functionalized thioimidazoles through a variant of the Marckwald
reaction.[12] Carbohydrate-derived amines were utilized in the
synthesis of cyclic depsipeptides,[13] neoglycoconjugates,[11a,b, 14]
and glycopeptidomimetics,[15] while structurally diverse
glycopeptidomimetics were also afforded utilizing carbohydrates
equipped with a carboxylic acid in the Ugi reaction.[16] Sugar
isocyanides have been sporadically used in MCRs, owing to a
challenging synthetic procedure, and low stability.[17] However,
recently we have successfully used 1-, 2-, and 6-isocyanoglycosyl
derivatives derivatives in the diastereoselective Passerini
reaction.[18] Although carbohydrate-derived aldehydes were often
[a]
Dr. K. Vlahoviček-Kahlina, Dr. K. Vazdar, Dr. I. Jerić
Division of Organic Chemistry and Biochemistry
Ruđer Bošković Institute
Bijenička cesta 54, 10000 Zagreb, Croatia
E-mail: ijeric@irb.hr
[b]
#
Dr. Z. Štefanić
Division of Physical Chemistry
Ruđer Bošković Institute
Bijenička cesta 54, 10000 Zagreb, Croatia
Current address: Faculty of Agriculture, University of Zagreb
Svetošimunska cesta 25, 10000 Zagreb, Croatia
Supporting information for this article is given via a link at the end of
the document.
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10.1002/cplu.202000177
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used in MCRs,[8,9] due to their reported influence on the
stereochemical outcome of the reactions, they are almost
neglected in isocyanide-based MCRs, a widely exploited strategy
for the generation of drug-like molecules. Of particular interest is
the Ugi reaction, where peptide-like structures, -
acylaminoamides can be prepared in a single step from suitable
building blocks equipped with an aldehyde, an amine, a carboxylic
acid and an isocyanide group. The Ugi reaction facilitates rapid
access to structurally diverse compound libraries, and is thus
exploited in diversity-oriented synthesis with application in drug
discovery.
All aldehydes were easily obtained by the oxidation of the
corresponding alcohols with Dess−Martin periodinane (details are
provided in the Supporting Information file). The selected
collection of aldehydes contains structurally diverse compounds
with aldehyde group attached to either tertiary carbon atom (in
aldehydes 1-4 and 7) or quaternary carbon atom (aldehydes 5
and 6). Selected aldehydes are in pyranose or furanose forms,
while aldehyde 4 is in open chain form.
Our initial experiments aimed on probing the robustness of
the selected methodology were performed with D-galactose
derived aldehyde 1. Formation of the Schiff base between an
aldehyde and an amine is the first step of the Ugi reaction;
therefore, we selected aromatic and aliphatic, chiral and achiral
components: benzyl amine, butyl amine, S-phenylethyl amine,
As
a part of our ongoing project on utilization of
carbohydrate-derived aldehydes in multicomponent reactions,[18]
in this study we evaluated the potential of the Ugi reaction in the
synthesis of various N-alkylated C-glycosyl amino acid derivatives. phenyl amine, and isopropyl amine in the reaction with acetic acid
N-Alkylation of amino acids and peptides is a valuable tool for
overcoming unfavorable pharmacokinetic properties of natural
peptides, mainly enzymatic degradation and limited ability to
cross biological membranes. N-Alkylation increases the
proteolytic stability towards enzymes, reduces the polar character
of the amide bond and often facilitates better interaction with
receptors by increasing rigidity of the peptide. Therefore, a robust,
single-pot access toward N-alkylated non-natural amino acid
building blocks is highly relevant for utilization in medicinal
chemistry.
and cyclohexyl isocyanide. All reactions were performed in
methanol at room temperature until the consumption of the
aldehyde was seen on TLC, typically for 6-24h. All five products
were isolated in very good yields, 75-85 % (products 1a-1e,
Scheme 3). Next, Ugi reactions were carried out with two
additional commercially available isocyanides, 1,1,3,3-
tetramethylbutyl isocyanide and methyl isocyanoacetate.
Products obtained from benzyl amine (1f) and butyl amine (1g
and 1h) were isolated again in very good yields, 70-76 %
(Scheme 3). Finally, along with simple acetic acid, three products
were obtained by using benzoic acid (1i, 72 %) fully protected N-
acetylmuramic acid (1j, 66 %) and dipeptide Boc-Phe-Ala-OH (1k,
63 %). Comparison of the results revealed that the reaction is
tolerant to different amines, carboxylic acids and isocyanides, and
highly robust; all products were obtained in very good yields, up
to 85 %. Diastereoselectivity of the Ugi reaction was determined
by the 1H NMR spectroscopy of the reaction mixture of the product
1b (80:20 d.r.); for all other products it was determined as the ratio
of isolated diastereoisomers. Only the major diastereoisomer of
product 1j was isolated, while the minor diastereoisomer partially
overlapped with the major one, therefore purification was
unsatisfactory. It is interesting to note that the d.r. remains almost
constant throughout all performed reactions, indicating the
predominant influence of the carbonyl component structure on the
diastereoselectivity outcome of the Ugi reaction.
Results and Discussion
We selected seven carbohydrate-derived aldehydes carrying one
or two isopropylidene-type of protecting groups: 1,2:3,4-di-O-
isopropylidene--D-galactopyranose-derived aldehyde 1, methyl-
2,3-O-isopropylidene--D-ribofuranoside-derived aldehyde 2, 3-
O-benzyl-1,2-O-isopropylidene-α-D-xylofuranose-derived
aldehyde 3, 2,3:4,6-di-O-isopropylidene-D-arabinose-derived
aldehyde 4, 2,3,4,5-di-O-isopropylidene β-D-fructopyranose-
derived
sorbofuranose-derived
aldehyde
5,
2,3:4,6-di-O-isopropylidene-α-L-
6, and 1,2:5,6-di-O-
aldehyde
isopropylidene--D-allofuranose-derived aldehyde 7 (Scheme 2).
Scheme 2. Selection of carbohydrate-derived aldehydes utilized in the Ugi
reaction.
To explore the substrate scope of the carbonyl components
in the Ugi reaction, we proceeded with a group of selected
isopropylidene-protected aldehydes (Scheme 2). In all further
experiments, acetic acid was the constant carboxylic component,
while benzylamine and butylamine were used in combination with
either cyclohexyl or 1,1,3,3-tetramethylbutyl isocyanide.
Reactions performed with methyl-2,3-O-isopropylidene--D-
ribofuranoside-derived aldehyde 2 furnished Ugi products 2a, 2b,
2f, and 2g in very good yields (72-79 %, Scheme 4), but with poor
diastereoselectivity, 54:46 d.r. Ugi products 3a, 3b and 3g derived
from 3-O-benzyl-1,2-O-isopropylidene-α-D-xylofuranose-related
aldehyde 3, were obtained in slightly lesser yields (62-69 %) but
with better diastereoselectivity; up to 69:31 d.r. (Scheme 4). An
open chain 2,3:4,6-di-O-isopropylidene-D-arabinose-derived
aldehyde 4 was utilized in the Ugi reaction giving products 4a, 4b,
and 4g in good yields (up to 71 %). The ratio of two
diastereoisomers was found to be constant, 65:35 d.r. in all three
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reactions performed with aldehyde 4. The next set of reactions
was carried out with D-fructose-derived aldehyde 5, where the
aldehyde group is attached to the quaternary carbon atom. Major
diastereoisomers were isolated for all three products (5a, 5f, and
5g) in 34-48 % yields, while purification of minor diastereoisomers
was not satisfactory due to the partial overlapping with the major
isomer and some reaction byproducts.
isomer was isolated in 59 % yield and purification of minor isomer
was again incomplete. Finally, in the reaction with 1,2:5,6-di-O-
isopropylidene--D-allofuranose-derived aldehyde 7 the major
isomer of the Ugi product 7a was isolated in 57 % yield.
Scheme 4. Products of the Ugi reaction performed with aldehydes 2-7.
Scheme 3. Products of the Ugi reaction performed with galactose-derived
aldehyde 1.
Obtained results allowed us to conclude that the applied
methodology is quite robust; it tolerates different amines and
isocyanides and provides access to α-acylamino carboxamides in
very good yields. Although observed diastereoselectivities are not
impressive, two diastereoisomers were separated and isolated as
pure compounds in most cases. Despite many efforts, to date, no
general solution for the problem of stereocontrol in the Ugi
Reaction performed with 2,3:4,6-di-O-isopropylidene-α-L-
sorbofuranose-derived aldehyde 6, acetic acid, benzyl amine and
cyclohexyl isocyanide furnished Ugi product 6a, where the major
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reaction has been found. The most promising results have been
obtained with either chiral amines in the four-component reaction
(U-4CR) or chiral imines in the three-component Ugi reaction (U-
3CR). Using this approach, reactions performed with chiral - and
-amino acids showed the best diastereoselectivities, while the
utilization of chiral aldehydes, acids or isocyanides generally gave
poor results.[19]
Finally, we examined further the utility of carbohydrate
aldehydes in the Ugi reaction by performing reactions with
bifunctional components to gain more complex structures. A
simple -amino acid, 3-aminopropanoic acid and more complex
-amino acid, protected muramic acid, were tested. Reactions
were carried out with galactose-derived aldehyde
1 and
cyclohexyl isocyanide in hexafluoroisopropanol (HFIP) at the
room temperature for 24 hours. Both products, 1n and 1o were
obtained in fair yields (64 % and 56 %, respectively) and 55:45
d.r. (Scheme 6). Next, we performed reaction with dipeptide H-
Phe-Leu-OH as bifunctional component. Ugi product 1p bearing
diketopiperazine ring was obtained in moderate yield (34 %) but
very good diastereoselectivity, 92:8 d.r. (Scheme 6).
To determine the influence of chiral -amino acids on the
diastereoselective outcome of the reaction, we performed the Ugi
reaction with L-valine tert-butyl ester, acetic acid, cyclohexyl
isocyanide and three different aldehydes. As presented in the
Scheme 5a, galactose-derived product 1l was obtained in 85 %
yield, with the ratio of two isolated distereoisomers d.r. 59:41.
Slight decrease in d.r. compared to other Ugi products in the
galactose series can be due to somewhat problematic purification
of the product 1l. Two diastereoisomers of the Ugi product 3l were
isolated in d.r. 65:35 and almost quantitative yield. Comparison
with other products obtained in the reaction with aldehyde 3
(Scheme 4), revealed that the influence of the chiral amine on the
diastereoselectivity is minimal. In the reaction with aldehyde 6 the
corresponding Ugi product 6l was isolated in 73 % yield and very
good diastereoselectivity, d.r. 86:14 (Scheme 5a). Finally, we
performed a three-component Ugi reaction with unprotected
valine as a bifunctional component (Scheme 5b). Ugi product 1m
was isolated in 58 % yield, and the ratio of two diastereoisomers
after purification was 75:25 d.r. Insight into obtained results with
chiral amines revealed that, contrary to the literature,[19] the
influence of the chiral amine components on the
diastereoselectivity of the Ugi reaction is unsubstantial and the
stereocontrol of the reaction is mainly determined by the chiral
aldehyde.
Scheme 6. Ugi products obtained with aldehyde 1, cyclohexyl isocyanide and
bifunctional derivatives.
Having the general scope of the Ugi reaction with different
aldehydes in hand, we probed the access to deprotected
derivatives. We selected Ugi products bearing different C-glycosyl
units to verify the robustness of the deprotection procedure.
Treatment of compounds 1a, 3a and 7a with TFA/H2O (9/1) at 0°
C resulted in removal of isopropylidene groups after 4 h, and
derivatives 8-10 were obtained in 70-77 % as a mixture of different
anomeric forms (Scheme 7).
A very important feature of peptides and peptidomimetics
with incorporated N-alkylated amino acids is their propensity to
adopt specifically folded secondary structures.[20] Turn-like
conformations are especially important in the design of
peptidomimetics aimed to target protein-protein and protein-
receptor interactions.[21,22] Turn-topology is mainly influenced by
the amino acid side-chain, therefore an access to structural motifs
able to induce different secondary structures is
a great
advantage.[23] We hypothesized that the combination of N-alkyl
substituent and the side-chain C-glycosyl unit will represent
interesting scaffolds able to mimic various peptide secondary
structures or induce new, abiotic ones. Access to such scaffolds
is highly relevant in the design of drug-like compounds and
materials with biomedical application. N-alkylation reduces the
Scheme 5. Ugi reactions performed with chiral amines; (a) a four-component
reaction with H-Val-OtBu; (b) a three-component reaction with H-Val-OH.
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number of hydrogen-bond donors, influences the cis–trans
equilibrium of the amide bond and increases steric hindrance,
thus affecting the conformational freedom of the adjacent amino
acids. Since our N-alkylated C-glycosyl amino acid derivatives are
too short to adopt stable secondary structure in solution, we opted
for x-ray analysis in this early stage hoping to get some insight
into conformational space accessed by different derivatives. We
managed to prepare crystals suitable for the x-ray analysis of four
Ugi products 1b, 1n (galactose derivatives), 3a (xylose derivative),
and 5f (fructose derivative). The main crystallographic data are
given in Table 1, while a more detailed data report is given in the
Supplementary Information file. Structures are presented at
Figure 1.
Table 1. Crystallographic and refinement data for compounds 1b, 1n, 3a, and
5f.
1b
1n
3a
5f
Formula
Formula
Weight
C25 H42 N2 O7 C22 H34 N2 O7 C31 H40 N2 O6 C30 H46 N2 O7
482.60
438.51
536.79
546.69
Crystal System
Space group
a, b, c [Å]
trigonal
P 32
22.0258(2)
22.0258(2)
15.1383(2)
orthorhombic monoclinic
monoclinic
P 21
P 212121
9.5087(2)
12.1237(3)
20.2845(6)
P 21
16.6779(4)
11.2365(3)
17.2990(5)
90
9.6708(3)
15.9475(3)
11.0762(3)
90 111.742(4)
90
α, , γ [°]
90 90 120
90 90 90
111.194(3) 90
V [Å3]
Z
6360.21(12) 2338.41(10) 3022.58(15) 1586.71(8)
9
4
4
2
D(calc) [g cm-3]
μ(CuKα) [mm-1]
F(000)
1.134
0.672
2358
1.246
0.765
944
1.180
0.659
1153
1.144
0.656
592
Crystal Size
[mm]
0.2x0.3x0.3 0.05x0.08x0.1 0.05x0.15x0.3 0.05x0.1x0.2
Scheme 7. Deprotection of selected Ugi products.
Structures 1b and 5f bearing galactose and fructose units,
respectively, have intramolecular hydrogen bonds between the
only available hydrogen bond donor (atom N2) and oxygen
acceptors on the sugar moiety (Table 2 and Figure 2). These
hydrogen bonds are bifurcated with O3 and O4 atoms as
acceptors in the structure 1b and more directional in structure 5f
where only oxygen O3 acts as an acceptor. In these two
structures, the intramolecular hydrogen bonds constrain and fix
the positioning of the sugar part of the molecule. Contrary to that,
structures 3a and 1n do not have intramolecular hydrogen bonds.
Instead, they form intermolecular N-H···O hydrogen bond with the
neighboring O1 acceptor. Thus, in case of the structure 3a two
molecules in asymmetric unit form a hydrogen bonded pair, while
only one hydrogen bond is present in structure 1n between
symmetrically related molecules in the crystal packing.
Figure 1. Thermal ellipsoid representation of the structures of compounds 1b, 1n, 3a
and 5f (at 50 % probability level). In case more than one molecule in asymmetric unit
is presented only one representative molecule is given. CCDC 1953263 (1b), 1953296
(1n), 1953294 (3a) and 1953283 (5f) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre.
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only amino acid that can readily adopt the conformations required
for the region (Figure 3).[24,25] Remarkably, our four structures fall
on very different positons on the plot, indicating the difference in
their conformation. The angle τ, torsional angles φ and ψ that
would correspond to Ramachandran torsional angles in protein
structures, are depicted on Figure 3 and listed in Table 3. Among
four structures, only the structure 1n falls into region allowed for
proteins, where -sheet structures are situated. It is possible that
the -sheet-like conformation in structure 1n is enforced by the
presence of four-membered ring C1-C2-N1-C11 which makes the
oxygen atom O1 point in the opposite direction with respect to O2,
quite like in the protein -sheet.
Table 3. Torsion angles , , and angle  (deg) for compounds 1b, 1n, 3a, and
5f as determined by X-ray crystallographic analysis.position
Figure 2. Hydrogen bonds in structures 1b, 1n, 3a and 5f.
φ (C2-N1-C3-C4)
53.2(3)
ψ (N1-C3-C4-N2)
-142.6(2)
τ (N1-C3-C4)
110.3(2)
Table 2. Hydrogen bond distances and angles in structures 1b, 1n, 3a, and 5f.
1b
55.4(3)
58.5(3)
-145.4(3)
-149.5(3)
110.26(19)
110.1(2)
Hydrogen bond
d(D-H) [Å]
d(H-A) [Å]
d(D-A) [Å]
angle(D-H-
A) [°]
1n
3a
-135.2(3)
132.3(2)
109.74(17)
structure 1b
2.0900
131.7(3)
127.3(3)
-54.8(3)
-48.3(5)
111.1(2)
111.7(2)
N2H2···O3
0.86
0.86
0.86
0.86
0.86
2.776(3)
2.816(4)
3.301(4)
2.800(3)
3.429(3)
137.00
132.00
168.00
131.00
170.00
N2AH2A···O3A
N2AH2A···O4A
N2BH2B···O3B
N2BH2B···O7B
2.1700
2.4600
2.1600
2.5800
5f
124.8(3)
104.7(3)
110.5(2)
structure 1n
2.1800
N2H2···O1
0.86
3.017(4)
163.00
structure 3a
2.1000
N2H2···O1A
N2AH2A···O1
0.86
0.86
2.926(4)
3.088(5)
161.00
164.00
2.2500
structure 5f
2.0900
N2H2···O3
0.86
2.826(3)
137.00
To compare structures of compounds 1b, 1n, 3a and 5f with
those deposited in Cambridge Crystallographic Database (CSD
version 5.40 with updates up to May 2019) we performed the
search using the query given on Figure SI-1. The care was taken
for the query to be sufficiently general to yield enough structures
for good statistics and to match the structures of our compounds
as close as possible. The search returned 1294 hits with 3438
substructure matches with selected query. The scatter plot of the
structures in the CSD search closely resembles the
Ramachandran plot of protein structures (Figure 3). This is mainly
a consequence of a large number of modified peptides present in
the CSD database, which naturally follow the most common
secondary structures of proteins. The structures in the search
predominantly populate four distinct areas of the plot, which
correspond to right handed and left handed α-helix structure, -
sheet and one area sparsely populated in proteins, which reflects
a fairly extended chain and is largely populated by glycine, the
Figure 3. The graphical representation of the results of the CSD analysis
corresponding to Ramachandran plot for polypeptides and protein strucutres.
The regions usually populated in proteins are denoted as αL (left-handed α-
helix), αR (right-handed α-helix) and  (for -sheets). It is visible that the
structures described in this paper cover completely different parts of the plot,
and only the structure 1n falls into the  region allowed for proteins.
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stirred for one hour at RT. To this reaction mixture was further added acid
(1.1eq) and isocyanide (1.1eq). The resulting mixture was stirred at RT
until the consumption of aldehyde was seen by TLC. The reactions were
concentrated under reduced pressure and the reaction mixtures purified
by flash column chromatography.
The importance of “3D-structural diversity“ to cover the
broad array of peptide secondary structures during the
peptidomimetic design, was nicely demonstrated by Shuto et
al.[26] Computational calculations and x-ray crystallography
studies showed that the incorporation of cyclopropane moiety
effectively constrains the molecular conformation of the peptide.
They prepared a group of cyclopropane-based peptidomimetics
mimicking a wide range of peptide secondary structures, from
folded to extended forms. Based on these analyses, a lead
stereoisomer targeting melanocortin receptors was identified, and
its potency and selectivity were improved by further derivatization.
Furthermore, it was demonstrated that peptide-based catalysts,[27]
nowadays implemented in myriad synthetically relevant
transformations, can access diverse conformational space, and
that low-barrier interconversions between conformations can be
an advantage in multistep, enantioselective reactions.[28] Thus,
supported by a strong literature precedent we plan to validate the
utility of here described N-alkylated C-glycosyl scaffolds as
inducers of various secondary structures. They will be
incorporated in short peptide sequences and their conformational
preferences in solid state and solution will be studied in details.
Representative example of the Ugi product:
2-(N-benzylacetamido)-N-cyclohexyl-2-((3aR,5S,5aS,8aS,8bR)-
2,2,7,7-tetramethyltetrahydro-3aH-bis([1,3]dioxolo)[4,5-b:4',5'-
d]pyran-5-yl)acetamide (1a) Yield 78 % (32 mg); colorless oil; Rf (DS1)
= 0.44, Rf (DS2) = 0.27 (EtOAc/PE 1:1, v/v); d.r. 78:22. Chemical shifts for
major isomer: 1H NMR (CDCl3): δ 7.51 – 7.25 (m, 5H), 6.99 (d, J = 6.6 Hz,
1H), 5.53 (d, J = 5.0 Hz, 1H), 4.91 (d, J = 8.8 Hz, 1H), 4.73 (d, J = 16.5 Hz,
1H), 4.64 – 4.52 (m, 2H), 4.29 (dd, J = 5.0, 2.4 Hz, 1H), 4.18 (dd, J = 8.0,
1.4 Hz, 1H), 3.82 – 3.61 (m, 2H), 2.07 (s, 3H), 1.88 (dd, J = 26.0, 11.9 Hz,
2H), 1.67 (s, 3H), 1.58 (s, 3H), 1.35 (s, 3H), 1.31 (s, 3H), 1.30 (s, 3H), 1.15
(m, 5H). 13C NMR (CDCl3) δ 173.5, 168.1, 137.2, 128.6, 128.3, 127.7,
109.9, 109.4, 97.1, 71.1, 70.9, 70.8, 66.2, 48.7, 33.4, 33.0, 26.4, 26.0, 25.9,
25.3, 25.2, 25.1, 24.4, 23.0. Chemical shifts for minor isomer: 1H NMR
(CDCl3) δ 7.29 – 7.17 (m, 5H), 6.41 (s, 1H), 5.52 (d, J = 5.1 Hz, 1H), 4.70
(d, J = 17.4 Hz, 1H), 4.58 (dd, J = 7.7, 2.4 Hz, 2H), 4.56 – 4.49 (m, 1H),
4.40 – 4.33 (m, 2H), 4.31 (dd, J = 5.1, 2.5 Hz, 1H), 3.59 (m, 1H), 2.02 (s,
3H), 1.83 – 1.76 (m, 2H), 1.69 – 1.50 (m, 3H), 1.48 (s, 3H), 1.46 (s, 3H),
1.38 – 1.24 (m, 7H), 1.19 – 1.10 (m, 4H). 13C NMR (CDCl3): δ 167.9, 137.9,
128.9, 127.4, 126.8, 109.7, 109.0, 96.8, 71.6, 71.5, 71.3, 70.8, 65.1, 48.3,
32.9, 26.4, 26.1, 25.8, 25.2, 24.9, 24.8, 22.8. HRMS (MALDI TOF/TOF):
Calcd. For C28H40N2O7 [M+H]+ 517.2914; found 517.2891.
Conclusions
We have prepared a library of N-alkylated C-glycosyl amino acid
derivatives comprising seven different isopropylidene-protected
carbohydrate motifs utilizing the four-component Ugi reaction.
The methodology tolerates different amines and isocyanides and
provide access to α-acylamino carboxamides in yields up to 82 %.
The stereochemical outcome of the reaction is mainly determined
by the nature of chiral, bulky, carbohydrate-derived aldehyde
components with the best diastereoselectivity being 80:20 d.r.
observed with galactose-related aldehydes. To validate the utility
of carbohydrate-derived aldehydes in accessing higher
complexity structures, we also performed three-component Ugi
reactions with bifunctional derivatives, and obtained Ugi products
bearing an additional ring in fair yields. Access to deprotected
derivatives was verified by acid-mediated removal of
isopropylidene groups performed on three Ugi products bearing
different C.glycosyl units. Since N-alkylated amino acids
derivatives are versatile scaffolds known to induce different folded
conformations, we performed single crystal x-ray analysis on
selected Ugi products comprising three different C-glycosyl units
to probe the conformational space accessible by these scaffolds.
Comparison of angle τ, and torsional angles φ and ψ revealed
large conformational differences between four structures, which
may be exploited in the design of oligomers able to adopt different
secondary structures.
Supplementary Information file contains experimental details for all
synthesized compounds, their 1H and 13C NMR spectra and
crystallographic data.
Acknowledgements
We are grateful for financial support from the Croatian Science
Foundation, Grant number 3102.
Keywords: amino acids • carbohydrates • C-glycosides •
peptidomimetics • Ugi reaction
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N-alkylated C-glycosyl amino acid
derivatives accessed by one-pot-four
component Ugi reaction
We describe a one-pot four-component methodology toward a library of N-alkylated
C-glycosyl amino acid derivatives comprising seven different isopropylidene-
protected carbohydrate units. The applied methodology provides access to Ugi
products in yields up to 85 %.
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