A multiple multicomponent approach to chimeric peptide-peptoid podands

Article abstract of DOI:10.1002/chem.201201591

The success of multi-armed, peptide-based receptors in supramolecular chemistry traditionally is not only based on the sequence but equally on an appropriate positioning of various peptidic chains to create a multivalent array of binding elements. As a faster, more versatile and alternative access toward (pseudo)peptidic receptors, a new approach based on multiple Ugi four-component reactions (Ugi-4CR) is proposed as a means of simultaneously incorporating several binding and catalytic elements into organizing scaffolds. By employing α-amino acids either as the amino or acid components of the Ugi-4CRs, this multiple multicomponent process allows for the one-pot assembly of podands bearing chimeric peptide-peptoid chains as appended arms. Tripodal, bowl-shaped, and concave polyfunctional skeletons are employed as topologically varied platforms for positioning the multiple peptidic chains formed by Ugi-4CRs. In a similar approach, steroidal building blocks with several axially-oriented isocyano groups are synthesized and utilized to align the chimeric chains with conformational constrains, thus providing an alternative to the classical peptido-steroidal receptors. The branched and hybrid peptide-peptoid appendages allow new possibilities for both rational design and combinatorial production of synthetic receptors. The concept is also expandable to other multicomponent reactions. Copyright

Full text of DOI:10.1002/chem.201201591

FULL PAPER
DOI: 10.1002/chem.201201591
A Multiple Multicomponent Approach to Chimeric Peptide–Peptoid
Podands
Daniel G. Rivera,[a, b] Fredy Leꢀn,[a] Odette Concepciꢀn,[b] Fidel E. Morales,[b] and
Ludger A. Wessjohann*[a]
Abstract: The success of multi-armed,
peptide-based receptors in supramolec-
ular chemistry traditionally is not only
based on the sequence but equally on
an appropriate positioning of various
peptidic chains to create a multivalent
array of binding elements. As a faster,
more versatile and alternative access
toward (pseudo)peptidic receptors, a
new approach based on multiple Ugi
four-component reactions (Ugi-4CR) is
proposed as a means of simultaneously
incorporating several binding and cata-
lytic elements into organizing scaffolds.
By employing a-amino acids either as
the amino or acid components of the
Ugi-4CRs, this multiple multicompo-
nent process allows for the one-pot as-
sembly of podands bearing chimeric
peptide–peptoid chains as appended
arms. Tripodal, bowl-shaped, and con-
cave polyfunctional skeletons are em-
ployed as topologically varied plat-
forms for positioning the multiple pep-
tidic chains formed by Ugi-4CRs. In a
similar approach, steroidal building
blocks with several axially-oriented iso-
cyano groups are synthesized and uti-
lized to align the chimeric chains with
conformational constrains, thus provid-
ing an alternative to the classical pepti-
do-steroidal receptors. The branched
and hybrid peptide–peptoid ap
ACHTUNGTRENNUNGpend-
AHCTUNGTRENNaGUN ges allow new possibilities for both ra-
tional design and combinatorial pro-
duction of synthetic receptors. The con-
cept is also expandable to other multi-
component reactions.
Keywords: multicomponent reac-
tions · steroids · supramolecular
chemistry · synthetic receptors · Ugi
reaction
Introduction
spherical ions, but are in general ineffective for more com-
plex substrates like small organic molecules or biomolecules.
Indeed, selective and efficient recognition processes for
these latter substrates require complex, multivalent recep-
tors capable to exert biomimicry through a multifaceted
binding behavior.[1,3,4] This concept has been successfully im-
plemented by creating chimeric receptors, that is, multi-
motif entities capable to exert the recognition process based
either on multivalent,[1] cooperative[3] or allosteric[4] effects
derived from the simultaneous participation of hybrid or-
ganic or metallo-(bio)molecular frameworks. Nevertheless,
the quest to achieve these remarkable hybrid entities always
comprises very elaborate, stepwise syntheses that focus on
the sequential incorporation of varied recognition or catalyt-
ic motifs, with the consequence of high cost or time owing
to the long synthetic routes.
The development of new strategies for the construction of
synthetic receptors and ligands has attracted significant at-
tention in the last decades. The creation of new, efficient
complexing agents for ions or larger organic molecules is
based on the concepts of either rational design[1] or on com-
binatorial methods.[2] Despite the immense progress ach-
ieved, both the binding prediction and the fast and efficient
incorporation of multiple binding functionalities into recog-
nition frameworks remain truly challenging. Most rapid and
straightforward approaches toward synthetic receptors pro-
duce homo-oligomeric or highly repetitive compounds, usu-
ally suitable for binding either simple, achiral guests or
Accordingly, synthetic approaches that rapidly and effi-
ciently generate complex multifunctional binding sites tai-
AHCTUNGTREGlNNNU ored for complex and chiral substrates are in high demand,
[a] Dr. D. G. Rivera, F. Leꢀn, Prof. Dr. L. A. Wessjohann
Department of Bioorganic Chemistry
Leibniz Institute of Plant Biochemistry
Weinberg 3, 06120 Halle/Saale (Germany)
Fax : (+49)345-5582-1309
for example, in the areas of catalyst and receptor design, be-
cause they are expected to increase the number of relevant
hits. Owing to the unraveling way by which multicomponent
reactions (MCRs) can simultaneously incorporate several
chemical motifs into a single structure, their application in
this field holds significant promise. Of special interest is the
utilization of MCRs that either generate natural-like binding
elements by themselves or allow for the efficient incorpora-
tion of these. This is the case with isonitrile-MCRs,[5] which
are well-known for producing pseudo-peptidic (e.g., pep-
E-mail: wessjohann@ipb-halle.de
[b] Dr. D. G. Rivera, O. Concepciꢀn, F. E. Morales
Center for Natural Products Research
Faculty of Chemistry, University of Havana
La Habana 10400 (Cuba)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201591; including experimen-
tal procedures and spectroscopic data of the steroidal isocyanides and
1
representative H and 13C NMR spectra of intermediates and final
products.
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toids, depsipeptides) and peptidomimetic motifs (e.g., oxa-,
thia- and tetrazoles, diketopiperazines) in a diversity-orient-
ed manner.[6–8]
Results and Discussion
Previously we could demonstrate that multiple Ugi-4CRs
Here we report a completely new class of chimeric pep-
tide–peptoid podands, produced by an isonitrile-MCR-based
approach capable to assemble in one step several building
blocks that can carry recognition and catalytic motifs. The
multicomponent assembly process encompasses the use of
threefold Ugi four-component reactions[8,9] (Ugi-4CRs) on
polyfunctional, tripodal, and concave skeletons with known
propensity to position binding functionalities in a preorgan-
ized form. As shown in Scheme 1A, the simplest version of
allow rapid access to a plethora of macroACTHNGUTERNNU(G multi)cyclic archi-
tectures.[8,9] However, acyclic synthetic receptors can be
more versatile than macrocycles in recognition studies of
complex biomolecules,[2,11] mainly due to their easier accessi-
bility and functionalization with multiple binding motifs. Di-
lution, pseudo-dilution, or long reaction times are not man-
datory and their higher conformational freedom allows for
more induced fits. In the following, this broader scope of
multifold Ugi-4CRs in podand assembly is demonstrated by
the rapid functionalization of
platforms of proven success in
supramolecular chemistry and
catalysis.
A
comprehensively studied
class of polydentate amido po-
dands with numerous applica-
tions in supramolecular and co-
ordination chemistry is derived
from tris(2-aminoethyl)amine
(TREN, 1).[12] Depending on
the structural features installed
in the tripodal skeleton, TREN-
based podands complex either
anions or (transition) metal
cations, often under participa-
tion of the tertiary amine in
the coordination process (Fig-
Scheme 1. a) Ugi four-component reaction (Ugi-4CR). b) Approach to multivalent, hybrid podands and recep-
tors by threefold Ugi-4CRs with the incorporation of 10 building blocks.
AHCTUNGTRENNUNG
ure 1).[8,12]
the Ugi-4CR comprises the one-pot condensation of a pri-
mary amine, an oxo compound, a carboxylic acid and an iso-
nitrile to form a N-substituted dipeptide (a peptoid in the
broad sense). When using amino acids either as the amino
or carboxy components of this reaction, the chemical moiety
formed can be regarded as a peptide–peptoid hybrid.[7,10]
Peptoids are non-natural surrogates of peptides that contain
Figure 1. Dual complexation capability of TREN-based podands.
the side-chain derivatization at the nitrogen of the amide in-
stead of the a-carbon. They may mimic many of the well-
known recognition and coordination properties of peptides,
such as: the chelation of cations by the amide bonds and
binding to neutral molecules by means of hydrogen bond-
ing.[10] Scheme 1B illustrates the prospect of the multiple
multicomponent (mMCR) approach that produces multiva-
lent frameworks by incorporating 10 building blocks in a
single step. A key feature of this approach is the rapid
access to a wide diversity of peptide–peptoid hybrid archi-
tectures by taking advantage of both the many commercial
building blocks available with amino or carboxylic acid func-
tions and the easy installation of isonitrile groups on readily
available tripodal and concave scaffolds. Formaldehyde is
commonly selected as oxo component with the aim to avoid
the formation of diastereomers as well as to be firmly fixed
to the definition of peptoids (i.e., N-substituted polyglycines
as peptoids in the strictest sense).
An analogous tripodal skeleton is also available as triacid
3, and in addition, triamine 1 can be easily converted into
triisonitrile 6 through the traditional formylation and dehy-
dration protocols to isonitriles.[8b] Table 1 shows the use of
these three tripodal platforms to produce chimeric peptide–
peptoid podands by using threefold Ugi-4CRs with mono-
protected a-amino acids acting either as the amino or car-
boxy components. The podands shown incorporate a-amino
acids of established recognition or catalytic behavior, that is,
glutamine (in 2), phenyl alanine (in 4), serine (in 5), histi-
dine (in 7), and proline (in 8). They are but a selection of
the more than 25 examples of TREN-based podands pro-
duced by parallel multicomponent synthesis for future rec-
ognition studies. All proteinogenic a-amino acids can be in-
corporated into podand architectures in a multifold manner,
of which only very few require additional protection[6e,13] for
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Chimeric Peptide–Peptoid Podands
FULL PAPER
Table 1. One-pot assembly of chimeric peptide–peptoid podands by threefold Ugi-4CRs of tripodal scaffolds
ter of the peptoid moieties
branched close to the nitrogen
head group, which hampers the
completion of the threefold
multicomponent process even
with small amino acids and iso-
nitriles. Evidence of this was
found by following the reaction
course by ESI-MS analysis,
which shows that the limiting
step is not the formation of the
third imine moiety but its par-
ticipation in the third Ugi-4CR
once the two initial peptoid
chains are formed. As a result,
good yields with triamine 1 re-
quire much longer reaction
times than with triacid 3 or tri-
with a-amino acid moieties of recognition and catalytic relevance.[a]
Tripodal core
Appendages
Chimeric podand
Yield [%]
56
73
AHCTUNGTERGiNNUN sonitrile 6, and even so, still
significant amounts (20–25%)
of the twofold Ugi-4CR-based
products were obtained as by-
products.
57[b]
It must be noted that peptoid
chains, as seen from the head
group of the tripodal skeleton,
can run either from N- to C-ter-
minus or vice versa. The use of
the three types of trifunctional
platforms enables all combina-
tions of threefold Ugi-4CRs to
take place, with the consequen-
tial increase of podand diversity
derived from three different
kinds of peptoid branching and
directionalities, even with other-
wise identical side-chain func-
tionalities (cf., the conceptually
identical, detailed discussion of
such directional and regioiso-
merism for macrocycles in
ref. [14]). Specificity and direc-
tionality of electrostatic interac-
tions such as hydrogen bonding
and ion pairing are extremely
important in selective supramo-
lecular complex formation. Ac-
64
76
[a] All reactions were conducted in MeOH at room temperature using formaldehyde as the oxo component.
[b] Yield over two steps.
side chains known to interfere with the normal course of the
Ugi-4CR (i.e., arginine, lysine, aspartic, and glutamic acid).
All chimeric peptide–peptoid podands were obtained in
good yields considering the formation of 12 new covalent
bonds in a single synthetic operation. Indeed, the procedure
can be considered well-suited for the combinatorial synthe-
sis of ligands and receptors as a result of its relatively high
chemical efficiency and rapid generation of structural diver-
sity. Triamine 1 afforded the lowest yields among a whole
set of center pieces. This might be due to the bulky charac-
cordingly, the easy access to counter running peptidic recog-
nition patterns is a key feature for studies of biomimetic
binding processes.
In addition to the variations of peptide and peptoid orien-
tation and that provided by canonical amino acids, the scope
of this multicomponent approach is boosted by the wide set
of other available building blocks that contain Ugi-reactive
functional groups. Scheme 2 depicts the synthesis of steroid-
armed podands 11 and 12 as examples for the application of
non-amino acid building blocks with proven relevance in
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L. A. Wessjohann et al.
Scheme 2. One-pot assembly of cholane-armed podands by threefold Ugi-4CRs with a tripodal triisonitrile.
recognition studies. They were obtained by employing tripo-
dal triisonitrile 6 and cholanic derivatives presenting carbox-
ylic acid (9) and amino (10)[15] groups that allow for the
Ugi-type multicomponent assembly. Especially the rigid and
concave scaffold of bile acids has been widely exploited in
supramolecular chemistry[16] and for the construction of ste-
gopeptides[19,22] and proteins.[20] Accordingly, we envisaged
the application of the multiple multicomponent approach to
the construction of chimeric peptide–peptoid podands fea-
turing topologically diverse preorganizing platforms.
Scheme 3 exemplifies the use of the bowl-shaped cyclotri-
veratrylene (CTV)-based triacid 13[19f,g] and the flat-type
Kempꢂs triacid 15[21] as templates for the one-pot assembly
ACHTUNGTRENNUNG
roidal conjugates with biological applications.[17] The incor-
poration of cholic acid (9) into the tripodal podand 11
worked well (61% yield), considering the extremely com-
plex and large structure formed in one step. In contrast, the
use of the 3a-cholanyl amine 10 afforded the cholane-armed
podand 12 in only 32% yield, showing that the attachment
of multiple cholanic arms at the sterically hindered position
3 is more difficult than at the highly flexible side-chain. In-
terestingly, the final yield of podand 12 could not be im-
proved even after prolonged reaction time (2 days), with the
consequent isolation of the corresponding two-armed inter-
mediate in up to 11% yield. The interest to access multi-
cholane-armed architectures in an efficient, straightforward
manner is based on their potential as molecular umbrellas,
that is, “amphomorphic” compounds that can produce a hy-
drophobic or hydrophilic exterior when exposed to a hydro-
phobic or hydrophilic microenvironment.[17a,c] This type of
scaffold has been successfully utilized for the transport of
bioACHTUNGTRENNUNGmolecules across membranes and to enhance the bio-
availability of drugs.[17a]
Besides the TREN-based tripodal architectures, there are
other types of concave, flat and cleft-type platforms with a
proven capability for positioning peptide motifs in a preor-
ganized form. Among them are the calixarenes,[18] cyclotri-
veratrylenes,[19] trialkylbenzenes,[20] Kempꢂs triacid,[21] and
varied steroidal skeletons as asymmetric examples.[16,22] The
conformational bias of these scaffolds allows for a specific
alignment of binding elements by directing them towards
the same side, a feature that has proven to be crucial for
mimicking the multivalent character of non-covalent inter-
actions in the biological realm. For example, by functionaliz-
ing these scaffolds with suitable peptidic chains, it has been
possible to mimic specific types of peptide foldings[21] as well
as different kinds of recognition and catalytic profiles of oli-
Scheme 3. Use of cyclotriveratrylene and Kempꢂs triacid as templates for
the one-pot assembly of aryl-armed, chimeric peptide–peptoid podands
by threefold Ugi-4CRs.
of multiple peptide–peptoid hybrid arms bearing aryl groups
at the chain tails. To our knowledge, chimeric peptide–pep-
toid podands based on Kempꢂs triacid template have been
the only type of hybrid peptidic podands produced so far,
albeit by traditional peptide-coupling protocols.[21d–f] It must
be mentioned that the lower yields of these latter entries
are not caused by the topology of the polyfunctional scaf-
folds but are due to the use of benzylisocyanide, a reagent
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Chimeric Peptide–Peptoid Podands
FULL PAPER
that is known to provoke side-reactions derived from its
moderate CH-acidity (see also podand 5 in Table 1). In ad-
dition to the examples shown, several others were synthe-
sized by varying the nature of the amino and isocyano com-
ponents, noting that the use of simpler, more nucleophilic
isonitriles like cyclohexyl and tert-butylisocyanide gave
yields over 70% in each case. Nevertheless, the examples
highlight the great versatility inherent to MCR-based
podand design, because it does not only enable the rapid
variation of the chemical nature of the appendages, but also
the easy installation of otherwise identical substituents into
dissimilar platforms. Since it is well-recognized that the re-
sulting binding profile is not only determined by the pres-
ence of the recognition motifs but especially by their appro-
priate three-dimensional arrangement, the possibility of
tuning both elements of diversity in a straightforward, paral-
lel fashion may be seen as the key feature of this methodol-
ogy towards the combinatorial construction of receptor and
ligand libraries.
for organizing multilateral functionalities suitable for pep-
tide and anion recognition is the steroid nucleus. Among the
different steroidal derivatives available for extensive func-
tionalization, the cholanic skeleton of bile acids has been
the most exploited one owing to its high availability and its
set of hydroxyl groups properly distributed along the con-
cave platform. Still and co-workers pioneered the use of this
scaffold for positioning peptidic chains in a combinatorial
fashion, aiming to achieve selective recognition of specific
oligopeptides.[22g,h] Meanwhile, the group of Davis has lead
the utilization of cholanic derivatives as organizing scaffolds
in podand-type anion receptors, namely cholapods.[23] The
general approach to achieve effective anion complexing
agents has been the replacement of the secondary hydroxyl
groups by stronger neutral or positively-charged hydrogen-
bond donor groups, such as: urea, thiourea, guanidinium,
and sulfonamide.
Along the way to position either hydrogen-bond donors
or peptidic chains, a common strategy has been the replace-
ment of the hydroxyls by amino groups.[22,23] Accordingly,
we envisaged that aminosteroids could be used (either by
themselves or through conversion to the corresponding iso-
cyanosteroids) as platforms for aligning chimeric peptide–
peptoid chains. Besides the curved 5b-cholanic scaffolds, it
was decided also to employ 5a-steroids with the aim of test-
ing a more extended and flatter polycyclic system. In terms
of conformational constrain, the advantage of employing an
A/B-trans steroidal nucleus containing all functionalities in
axial orientation has been well documented.[22g,24] However,
this has been only achieved by modifying the cis A/B-ring
fusion of bile acids.[24] Alternatively, we devised the use of
the naturally occurring spirostan and furostan sapogenins,
which possess the desired 5a-skeleton and are endowed with
functionalization sites on rings A, B, and C.
Despite the C3-symmetry of these podands, very complex
NMR spectra were observed as a result of the occurrence of
duplicate signals for the same set of atoms. The detection of
several conformers in solution derives from the cis/trans iso-
merization of the N-substituted amide bonds and is a typical
feature of peptoid chemistry. Certainly, the complexity of
these structures along with the various combinations of the
different N-substituted amide configurations makes it im-
1
possible to accomplish a detailed interpretation of H NMR
spectra. Thus, normally, duplicate sets of signals were detect-
ed for the amide carbon atoms in 13C NMR spectrum.
On the other hand, the well-known chemical outcome of
the Ugi-4CR along with a precise HR-ESI-MS analysis
allows for an unequivocal structural assignment of all chi-
meric podands. Although the incidence of several conform-
ers arising from the peptide–peptoid hybrid chains compli-
cates the spectroscopic analysis; this may be seen as advan-
tageous in terms of molecular recognition. Firstly, it must be
mentioned that the ease of cis/trans-isomerization does not
confer a greater flexibility of peptoid side-chains versus pep-
tide side-chains in general, quite the opposite is often
found: peptoids, especially N-alkylated peptides not based
on polyglycine, commonly have less conformational freedom
than peptides because the amide bond rotation is but one el-
ement in conformational space.[7] Secondly, the occurrence
of various low-energy conformations on the peptoid amide
bonds enables to populate a rather different and additional
conformational space than the one accessible with normal
peptide chains, with the consequence of a higher probability
to access a binding conformation not available for pep-
Scheme 4 shows the synthesis of spirostanic and furostanic
diisonitriles from the corresponding amino derivatives.[25]
Whereas procedures toward axial aminosteroids are well-es-
tablished,[26,27] the functionalization of steroids with various
axial isocyano groups has not been reported so far. Our ap-
proach started with the double formylation of the 3a,7a-di-
AHCTUNGTREGaNNNU mino-spirostane 17, previously prepared from the natural
sapogenin diosgenin according to a reported procedure.[25]
From the different formylation protocols reported for ali-
phatic amines, the use of ethyl or methyl formate heated at
reflux proved ineffective due to the low reactivity of both
axial amines, but the mixed formic-acetic anhydride method
afforded diformamide 18 in quantitative yield. This com-
pound was submitted to dehydration using the traditional
POCl3/Et3N procedure to furnish 3a,7a-diisocyano-spiro-
stane 19 in 81% yield, thus proving the efficiency of this
simple method also on steroids. The relative stereochemistry
of both isonitrile groups was confirmed by the narrow shape
of the multiplets assigned to the equatorial protons H-3b
ACHTUNGTRENNUNG
tides.[7] Thirdly, upon the presence of the same type of func-
tionalities, the branched character of the peptoid backbone
favors a higher functional density of the recognition ele-
ments than those with a linear disposition.[7]
After the grounds of the multiple multicomponent ap-
proach to assemble multivalent podands were established,
the focus was directed to adopt a rigid center piece in
mMCR-chemistry. The one that is most frequently utilized
1
and H-7b in the H NMR spectrum of 19. As expected, no
racemization was detected with this procedure.
For the preparation of a spirostanic steroid functionalized
with isocyano groups on rings A and C, we used a multi-
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L. A. Wessjohann et al.
Scheme 4. Synthesis of A, B) spirostanic diisonitriles and C) furostanic diisonitriles. a) HCO2H/Ac2O, then THF, Et3N; b) POCl3, Et3N, THF, ꢀ60!08C;
c) PCC, CH2Cl2; d) NH2OH, AcONa, MeOH, D; e) H2, PtO2, then Zn, AcOH; f) Boc2O, THF/aq. sat. NaHCO3; g) TFA, CH2Cl2; h) Ac2O, Py. Abbrevia-
tions: Boc=tert-butoxycarbonyl; PCC=pyridinium chlorochromate; TFA=
trifluoroacetic acid.
step approach previously developed by Davis and co-work-
ers[24,27] to introduce a-oriented amino groups in allocho-
lanes (i.e., A/B-trans cholanic substrates). Initially, the natu-
ral sapogenin hecogenin (20) was submitted to pyridinium
chlorochromate (PCC) oxidation to the corresponding di-
ACHTUNGTRENNUNGketone, followed by oximation to afford a dioxime inter-
mediate in 94% yield. This compound was subjected to a
two-step reduction by using PtO2-catalyzed hydrogenation
followed by treatment with Zn/AcOH to give the corre-
sponding spirostanic 3a,12a-diamine (22), which for storage
and better handling was then protected as the di-Boc deriva-
tive 21 in 73% overall yield. Comparative NMR analysis
confirmed the desired a stereochemistry of both amino
functions (as carbamates). In our hands, the C-3 epimer of
21 was also obtained as a minor byproduct (6%), whereas
the C-12 epimer was not detected. For isonitrile formation,
dicarbamate 21 was deprotected with 30% TFA/CH2Cl2 and
subsequently subjected to the previously standardized for-
mylation and dehydration protocols to furnish the 3a,12a-
Scheme 5. Synthesis of cholanic tri- and diisonitriles. a) Ac2O, Py;
b) TFA, CH2Cl2; c) HCO2H/Ac2O, then THF, Et3N; d) POCl3, Et3N,
THF, ꢀ60!08C; e) H2, 10% Pd/C, EtOH dry.
diisonitrile 23 in 75% yield. Similarly, the furostanic di
ACHTUNGTNERiNUNG so-
A
ed as acetate and the resulting tris-carbamate was submitted
sequentially to Boc-removal, formylation and finally to de-
hydration, without purification of the intermediates, to
afford the cholanic triisonitrile 27 in 63% yield over four
steps.
In a similar way, the Boc-protected amino-cholanes 28
and 30 were synthesized according to reliable procedures re-
ported by Davis and co-workers,[27] thus providing an array
of differentially positioned amino groups for the already
standardized conversion to isonitriles. Compound 28[27b] was
initially acetylated and next subjected to Pd-catalyzed hy-
drogenation to transform the 3a-azido group into an amine.
The remaining Boc group was then removed and the result-
ing diamine was submitted to formylation and subsequent
dehydration to afford the cholanic 3a,12a-diisonitrile 29 in
over four steps, that is, protection of the primary hydroxyl
group, di-Boc removal, formylation and dehydration exactly
as described before.
Scheme 5 shows the synthesis of cholanic polyisonitriles
from the corresponding aminocholanes. The cholic acid skel-
eton is naturally endowed with three functionalization sites,
a feature that enables a tunable variation of the position
and multiplicity of the Ugi-4CRs through conversion of the
hydroxyls into amino and isocyano groups. For example, the
tris-Boc cholanic derivative 26 was obtained from methyl
cholate according to the multi-step procedure developed by
Savage and co-workers,[26] who also confirmed the stereo-
chemistry of the Boc-protected amino groups by X-ray crys-
tallography. The primary hydroxyl of 26 was further protect-
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Chimeric Peptide–Peptoid Podands
FULL PAPER
58% yield over four steps. Di-Boc derivative 30[27a] was
equally deprotected, formylated, and dehydrated to furnish
the cholanic 7a,12a-diisonitrile 31 in 73% yield.
proline. Similarly, furostanic diisonitrile 25 was used for the
double incorporation of l-alanine methyl ester and N-Boc-
l-cysteine to furnish peptido-furostane 25 in 73% yield. The
high yields achieved in these examples demonstrate the
great efficiency of the multicomponent assembly process
even by using several axial isocyano groups derived from
the trans A/B-ring fusion systems. It also proves the feasibil-
ity of incorporating multiple organocatalytic (i.e., proline,
histidine, and thiols) and binding elements (e.g., hydroxyls,
thiol, and carboxylate) in a highly preorganized form caused
by the axial positioning of these appendages.
From the various reports that employ steroids in Ugi-
4CRs,[28] we are aware of only two examples that make use
of isocyanosteroids[14b,28a] and another two that use amino-
steroids.[14b,28d] However, those groups were attached either
to the flexible side or to the steroidal nucleus with an equa-
torial orientation, thereby lacking the reactivity problems
usually found in steroid chemistry with axial substituents.
But axially-oriented binding elements are preferred in rec-
ognition due to the better preorganization induced. Thus, it
was important to assess whether sterically hindered, axial
amino and isocyano groups are suitable reactants in complex
multiple multicomponent reactions. In the initial experi-
ments, steroids having axial isocyano groups afforded excel-
lent results, whereas those with axial amino groups gave
only moderate yields, rendering the latter ineffective for the
multifold-assembly process. A connected issue is the pros-
pect of a better recognition capability of the peptoid chain
derived from the isonitrile-based cores. As illustrated in Fig-
ure 2A, the use of aminosteroids furnishes a sterically
Of special interest is the incorporation of multiple indole,
benzyl, and imidazole side-chains. Chimeric peptido-cho-
AHCTUNGTRENNUNG
lanes derived from Na-Boc-protected l-tryptophan, l-histi-
dine, and L-phenylalanine on cholane polyisonitriles 27, 29,
and 31, respectively, formed readily, thereby offering a very
diverse array of chimeric peptide–peptoid chains attached to
a cis A/B-steroidal skeleton. Peptido-cholane 35, obtained
in 71% yield, provides a conformationally rigid arrangement
of three indole-containing appendages with the potential for
organic cation recognition. Similarly, peptido-cholanes 36
and 37 were produced in 82 and 77% yields. Once again,
the multiple Ugi-4CRs showed great chemical efficiency
with the sterically hindered 7a- and 12a isocyano groups, an
important feature for the future combinatorial production of
peptido–steroidal receptors. The same strategy is amenable
to solid-phase protocols when the carboxylic or hydroxyl
functions of the cholanic and furostanic side-chains are at-
tached to a resin bead or another surface, as implemented
with great success in solid-phase peptide synthesis.[22,25,29]
Compared with the general methodology used to produce
peptido–steroidal receptors through traditional peptide-cou-
plings, the present approach shows greater promise in terms
of speed, versatility, atom economy, and binding-motif-gen-
eration, especially if sequential approaches are implemented
for growing oligochimeric peptide–peptoid chains.[6e,9b,30] We
believe that the potential of the Ugi-4CR for complexity
generation is now unraveling towards the design of new
(pseudo-) peptide-based receptors. This becomes more
patent when considering that at least two amino acid units
can be incorporated into a rigid, organizing platform in each
condensation step, a number that is multiplied by two and
three depending on the multifold character of Ugi-4CRs. In
addition, our limitation to formaldehyde as oxo-component
of the Ugi-4CR is exclusively made for spectroscopic rea-
sons, but with other aldehydes the efficiency is even higher.
Also, the utilization of other oxo-components (e.g., amino
acid-derived aldehydes, ketones) introduces an additional
source of functional diversity (see Scheme 1), thus enhanc-
ing the multivalent character of the resulting branched, pep-
tide–peptoid hybrid arms.[9]
Figure 2. Comparison of the axially oriented, chimeric peptide–peptoid
chains resulting from the Ugi-4CR with a) an aminosteroid and b) an iso-
cyanosteroid. The figures represent the position 7a in a putative steroidal
skeleton either from the 5a or 5b series. PG=protecting group. R1 and
R2 =a-amino acid side chains. R3 =substituent of the isonitrile group.
crowded tertiary amide directly attached close to the bulky
steroidal skeleton, with no place for the internal binding of
a guest molecule if several such groups are placed on a rigid
host surface. In contrast, the use of isocyanosteroids leads to
a more convenient peptoid with a C!N directionality run-
ning from the steroid at the C-terminus to the N-terminus
(Figure 2B). This choice gives rise to a more rigid position-
ing of the hydrogen-bond donors, as the unsubstituted (pep-
tidic) amides are directly attached to the convergent a-face
of the steroidal basis, but at the same time allows more free-
dom for binding a guest. As a consequence of all this, we
suggest isocyanosteroids instead of aminosteroids to produce
potential peptidosteroidal receptors by means of multifold
Ugi-4CRs.
Table 2 depicts the multicomponent assembly of chimeric
peptide–steroids derived from spirostanic-, furostanic-, and
cholanic skeletons with mono-protected a-amino acids. Pep-
tido-spirostane 32 was obtained from diisonitrile 19 in 81%
by double incorporation of l-alanine methyl ester and N-
Boc-l-serine, whereas compound 33 was afforded from di-
Conclusion
The most relevant achievement of the multiple multicompo-
nent assembly process is the possibility to cover a large
ACHTUNGTRENNUNGisonitrile 23 in 88% yield by including two units of N-Cbz-l-
Chem. Eur. J. 2013, 19, 6417 – 6428
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L. A. Wessjohann et al.
Table 2. One-pot assembly of chimeric peptide–steroids by multifold Ugi-4CRs.[a]
Steroidal core Appendages
Chimeric peptide–steroid
Yield [%]
81
88
73
71
82
77
[a] All reactions were conducted in MeOH at room temperature using formaldehyde as the oxo component.
6424
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ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 6417 – 6428

Chimeric Peptide–Peptoid Podands
FULL PAPER
Podand 2: Triamine 1 (0.15 mL, 1.0 mmol), paraformaldehyde (90 mg,
3.0 mmol), N-Boc-l-glutamine (738 mg, 3.0 mmol) and cyclohexylisoni-
trile (0.37 mL, 3.0 mmol) were reacted according to the general threefold
Ugi-4CR-based procedure. Flash column chromatography purification
(CH2Cl2/MeOH 15:1) afforded podand 2 (698 mg, 56%) as a pale yellow
oil. 1H NMR (400 MHz, CDCl3; rotamers and broadened signals are de-
tected): d=7.68–7.40 (m, 3H, NH), 6.56 (brs, 2H, NH2). 6.48 (brs, 4H,
2ꢃNH2), 5.33–5.29 (m, 3H, 3ꢃNH), 4.57–4.53 (m, 3H, 3ꢃCH), 4.31–4.26
(m, 6H, 3ꢃCH2), 3.92–3.87 (m, 6H, 3ꢃCH2), 3.76 (m, 3H, 3ꢃCH), 3.25–
3.20 (m, 6H, 3ꢃCH2), 2.58–2.54 (m, 6H, 3ꢃCH2), 1.88 (m, 6H, CH2-cy-
clohex.), 1.76–1.64 (m, 12H, CH2-cyclohex.), 1.48–1.38 (m, 12H, CH2-cy-
clohex.), 1.47, 1.46, 1.45 ppm (3 s, 27H, 3ꢃ(CH3)3C); 13C NMR
(100 MHz, CDCl3): d=175.0, 174.8, 174.7, 171.9, 171.4, 171.2, 1170.6,
167,8, 167.6, 166.9, 154.9, 80.1, 77.3, 56.6, 53.5, 51.2, 50.8, 40.8, 40.1, 37.7,
28.5, 28.3, 28.1, 24.8, 22.7 ppm; IR (ATR): n˜ =3335, 3247, 3221, 2967,
2933, 1748, 1672, 1653, 1558, 1540, 1456, 1220 cmꢀ1; HRMS (ESI-FT-
chemical space of podand arms and topologies in fast one-
pot approaches with levels of chemical efficiency suitable
for automation. The examples presented herein are but a
glimpse of the structural diversity available by the combina-
tion of geometrically different organizing platforms (e.g., tri-
podal, cleft, and concave scaffolds) with the rapid genera-
tion of multiple appendages having variable side-chains.[13]
Moreover, the number of available podands is not limited to
the variation of platforms and functionalized arms, but the
N!C directionality and the endo/exo peptoid combinations
discussed previously can further enhance diversity.[9,14] Also,
podand arms do not need to be identical and can be assem-
bled by using combinatorial strategies previously applied to
macrocycles.[31] Another issue that boosts the versatility of
this concept is the plethora of other isonitrile- or even non-
isonitrile-based MCRs,[5,32] eventually followed by post-con-
densation modifications,[33] capable of introducing chemical
motifs with potential in recognition and catalytic processes
(e.g., nitrogen, sulfur and oxygen-containing heterocycles).
Future combinatorial and evolutionary strategies derived
from this concept may enhance discovery rates and lead to
the emergence of new families of receptors, catalysts, or bio-
logically active ligands based on MCR-motifs.
ICR): m/z calcd for C60H105NaO15N13
[M+Na]+.
: 1270.7752; found: 1270.7756
Podand 4: Triacid
3 (191 mg, 1.0 mmol), paraformaldehyde (90 mg,
3.0 mmol), l-phenylalanine methyl ester hydrochloride (647 mg,
3.0 mmol), Et3N (0.42 mL, 3.0 mmol), and tert-butylisonitrile (0.35 mL,
3.0 mmol) were reacted according to the general threefold Ugi-4CR-
based procedure. Flash column chromatography purification (CH2Cl2/
MeOH 18:1) afforded podand 4 (740 mg, 73%) as a pale yellow oil.
1H NMR (400 MHz, CDCl3; rotamers and broadened signal are detect-
ed): d=7.31–7.19 (m, 15H, 3ꢃPh), 4.04 (t, J=7.6 Hz, 1H, CH), 3.87–3.80
(m, 2H, 2ꢃCH), 3.74, 3.75, 3.75 (3 s, 9H, 3ꢃOCH3), 3.67 (m, 2H, CH2),
3.55 (m, 2H, CH2), 3.50 (m, 2H, CH2), 3.38–3.25 (m, 6H, 3ꢃCH2), 3.06–
3.00 (m, 2H, CH2), 2.91–2.81 (m, 2H, CH2), 2.77–2.69 (m, 2H, CH2),
131.1, 1.30, 1.29 ppm (3 s, 27H, 3ꢃ(CH3)3C); 13C NMR (100 MHz,
CDCl3): d=175.5, 170.9, 170.1, 169.8, 166.0, 137.2, 137.1, 129.3, 129.1,
129.0, 128.8, 128.5, 128.2, 126.8, 77.2; 64.7, 64.1, 54.8, 54.0, 52.9, 52.1, 51.6,
51.2, 50.3, 39.8, 34.6, 28.7, 28.6, 28.5 ppm; IR (ATR): n˜ =3329, 2977,
1742, 1735, 1982, 1667, 1639, 1204, 1167 cmꢀ1; HRMS (ESI-FT-ICR): m/z
calcd for C54H75NaO12N7: 1036.5370; found: 1036.5372 [M+Na]+.
Experimental Section
General remarks: Melting points were determined on a Leica DM LS2
apparatus and are uncorrected. 1H NMR and 13C NMR spectra were re-
corded on a Varian Mercury 400 spectrometer at 399.94 and 100.57 MHz,
respectively. Chemical shifts (d) are reported in ppm relative to the TMS
(1H NMR) and to the solvent signal (13C NMR). IR spectra were ob-
tained on a Bruker FT-IR spectrometer. High-resolution ESI mass spec-
tra were obtained from a Bruker Apex III Fourier transform ion cyclo-
tron resonance (FT-ICR) mass spectrometer equipped with an Infinity
cell, a 7.0 Tesla superconducting magnet, an RF-only hexapole ion guide,
and an external electrospray ion source (Agilent, off axis spray). ESI-MS
was recorded on a Finnigan TSQ 7000, LC-Tech Ultra Plus pumps,
Linear UV/Vis 200 detector, Sepserve Ultrasep ES RP-18 5 mm 1ꢃ
100 mm column (flow 70 mL minꢀ1). Flash column chromatography was
carried out using Merck silica gel 60 (0.015–0.040 nm) and analytical thin
layer chromatography (TLC) was performed using Merck silica gel 60
F254 aluminum sheets. Solid compounds were recrystallized from selected
solvents for the melting point measurements. All commercially available
chemicals were used without further purification. The syntheses of the
isocyanoesteroids 19, 23, 25, 27, 29, and 31 are described in the Support-
ing Information.
Podand 5: Triacid
3 (191 mg, 1.0 mmol), paraformaldehyde (90 mg,
3.0 mmol), tert-butyl l-serine methyl ester hydrochloride (636 mg,
3.0 mmol), Et3N (0.42 mL, 3.0 mmol), and benzylisocyanide (0.27 mL,
3.0 mmol) were reacted according to the general threefold Ugi-4CR-
based procedure. The resulting crude product was dissolved in dry
CH2Cl2 (10 mL) and treated with trifluoroacetic acid (5 mL) at 08C. The
reaction mixture was stirred at room temperature for 2 h and then con-
centrated under reduced pressure. TFA was removed completely by re-
petitive addition and evaporation of CH2Cl2. Flash column chromatogra-
phy purification (CH2Cl2/MeOH 15:1) afforded podand 5 (532 mg, 57%)
as a colorless oil. 1H NMR (400 MHz, CDCl3; rotamers and broadened
signals are detected): d=8.03 (m, 2H, 2ꢃNH), 7.11 (t, J=5.4 Hz, 1H,
NH), 7.31–7.24 (m, 15H, 3ꢃPh), 5.33 (m, 3H), 5.18 (m, 3H), 4.83 (m,
3H), 4.58 (m, 3H), 4.51–4.39 (m, 6H, 3ꢃCH2), 4.35–4.20 (m, 6H, 3ꢃ
CH2), 4.08–3.97 (m, 6H, 3ꢃCH2), 3.93–3.70 (m, 6H, 3ꢃCH2), 3.72, 3.70,
3.68 ppm (3 s, 9H, 3ꢃOCH3); 13C NMR (100 MHz, CDCl3): d=170.5,
170.3, 170.1, 169.7, 168.8, 168.7, 137.3, 137.2, 128.6, 127.8, 127.6, 127.5,
61.8, 61.5, 59.6, 59.5, 53.5, 52.7, 52.6, 49.8, 47.7, 43.8, 42.8 ppm; IR
(ATR): n˜ =3352, 3398, 3010, 2968, 1743, 1732, 1678, 1652, 1639, 1108,
General multifold Ugi-4CR-based procedure: The molarities in the fol-
lowing procedure are based on one Ugi-reactive group, see note (2)
1067, 1056, 910 cmꢀ1
;
HRMS (ESI-FT-ICR): m/z calcd for
below.
A suspension of the aldehyde (1.0 mmol) and the amine
C45H57NaO15N7: 958.3811; found: 958.3819 [M+Na]+.
(1.0 mmol) was stirred in MeOH (50 mL) at room temperature until a
clear solution was achieved (usually from 1 to 3 h). The carboxylic acid
(1.0 mmol) and the isonitrile (1.0 mmol) were subsequently added and
the stirring was continued for an additional 12 h. The volatiles were then
evaporated under reduced pressure and the resulting crude material was
purified by flash column chromatography on silica gel to afford the corre-
sponding podand. Notes: 1) Et3N (ꢁ1.0 mmol) may be required for the
formation of the imine when the amino component is employed as hy-
drochloride salt (e.g., a-amino acid methyl ester hydrochlorides). 2) The
molarities of the polyfunctional building blocks (i.e., triamines, triacids,
di- and triisonitriles) have to be adapted to 1/3 or 1/2 of the monofunc-
tional ones, keeping the order of addition of amine and aldehyde, fol-
lowed by acid and finally isonitrile.
Podand 7: Triisonitrile 6 (176 mg, 1.0 mmol), paraformaldehyde (90 mg,
3.0 mmol), glycine methyl ester hydrochloride (375 mg, 3.0 mmol), Et3N
(0.42 mL, 3.0 mmol), and Na-Cbz-l-histidine (867 mg, 3.0 mmol) were re-
acted according to the general threefold Ugi-4CR-based procedure. Flash
column chromatography purification (CH2Cl2/MeOH/Et3N 10:1:0.1) af-
1
forded podand 7 (862 mg, 64%) as a pale yellow oil. H NMR (400 MHz,
CDCl3): d=7.32 (m, 3H, 3ꢃCH-imid.), 7.29 (m, 15H, 3ꢃPh-Cbz), 6.74
(m, 3H, 3ꢃCH-imid.), 5.39 (s, 3H, 3ꢃNH), 5.10 (brs, 6H, 3ꢃCH2), 4.45
(m, 3H, 3ꢃCH), 4.25–4.18 (m, 6H, 3ꢃCH2), 4.02–3.94 (m, 6H, 3ꢃCH2),
3.87–3.81 (m, 6H, 3ꢃCH2), 3.75, 3.74 (2 s, 9H, 3ꢃOCH3), 3.24–3.20 (m,
6H, 3ꢃCH2), 2.55 ppm (m, 6H, 3ꢃCH2); 13C NMR (100 MHz, CDCl3):
d=170.1, 169.7, 169.6, 168.5, 156.2, 139.2, 136.3, 135.7, 128.4, 127.9, 127.8,
Chem. Eur. J. 2013, 19, 6417 – 6428
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L. A. Wessjohann et al.
117.0, 116.9, 70.2, 66.8, 54.2, 51.8, 49.6, 52.4, 43.4, 37.5 ppm; IR (ATR):
n˜ =3064, 2955, 1734, 1731, 1694, 1683, 1665, 1206, 1202, 1158 cmꢀ1
1.5 mmol) were reacted according to the general threefold Ugi-4CR-
based procedure. Flash column chromatography purification (CH2Cl2/
MeOH 15:1) afforded podand 16 (253 mg, 53%) as a white solid. M.p.
(from MeOH): 170–1728C; 1H NMR (400 MHz, CDCl3): d=7.92 (m,
15H, 3ꢃPh), 7.69 (m, 3H, 3ꢃNH), 4.54–4.47 (m, 3H, 3ꢃCH), 3.95–3.92
(m, 6H, 3ꢃCH2), 3.76, 3.74, 3.73 (3 s, 9H, 3ꢃCH3O), 3.41–3.37 (m, 6H,
3ꢃCH2), 2.45 (d, J=12.6 Hz, 3H, CH2), 2.37 (d, J=14.0 Hz, 3H, CH2),
1.19 (s, 9H, 3ꢃCH3), 1.08–0.99 ppm (m, 6H, 3ꢃCH2); 13C NMR
(100 MHz, CDCl3): d=172.0, 170.4, 170.1, 169.8, 138.2, 125.7, 124.9,
122.9, 51.5, 51.3, 48.1, 44.2, 42.3, 30.8, 21.3 ppm; HRMS (ESI-FT-ICR):
m/z calcd for C51H66NaO12N6: 977.4637; found: 977.442 [M+Na]+.
;
HRMS (ESI-FT-ICR): m/z calcd for C63H78NaN16O18: 1369.5579; found:
1369.5574 [M+Na]+.
Podand 8: Triisonitrile 6 (176 mg, 1.0 mmol), paraformaldehyde (90 mg,
3.0 mmol), glycine methyl ester hydrochloride (375 mg, 3.0 mmol), Et3N
(0.42 mL, 3.0 mmol), and N-Cbz-l-proline (747 mg, 3.0 mmol) were react-
ed according to the general threefold Ugi-4CR-based procedure. Flash
column chromatography purification (CH2Cl2/MeOH 12:1) afforded
podand 8 (931 mg, 76%) as a pale brown oil. 1H NMR (400 MHz,
CDCl3; rotamers and broadened signals are detected): d=7.37–7.30 (m,
15H, 3ꢃPh-Cbz), 5.13–5.00 (m, 6H, 3ꢃCH2), 4.74–4.46 (m, 3H, 3ꢃCH),
4.21–4.09 (m, 6H, 3ꢃCH2), 3.78, 3.77, 3.75 (3 s, 9H, 3ꢃOCH3), 3.63–3.49
(m, 12H, 6ꢃCH2), 3.32–3.24 (m, 6H, 3ꢃCH2), 2.53 (m, 6H, 3ꢃCH2),
2.28–2.12 (m, 6H, 3ꢃCH2), 2.00–1.91 ppm (m, 6H, 3ꢃCH2); 13C NMR
(100 MHz, CDCl3): d=173.8, 170.8, 170.4, 168.5, 154.9, 136.5, 128.4,
127.9, 127.7, 127.5, 66.9, 56.5, 53.0, 52.5, 50.6, 46.8, 45.5, 38.2, 29.8,
24.0 ppm; IR (ATR): n˜ =3317, 3064, 2953, 1697, 1693, 1635, 1467, 1248,
Spirostanic peptide–peptoid hybrid 32: Diisocyanide 19 (225 mg,
0.5 mmol), paraformaldehyde (30 mg, 1.0 mmol), N-Boc-l-serine
(205 mg, 1.0 mmol), l-alanine methyl ester hydrochloride (139 mg,
1.0 mmol), and Et3N (0.14 mL, 1.0 mmol) were reacted according to the
general polyfold Ugi-4CR-based procedure. Flash column chromatogra-
phy purification (CH2Cl2/MeOH 12:1) afforded 32 (417 mg, 81%) as a
white solid. M.p. (from MeOH): 178–1798C; 1H NMR (400 MHz,
CDCl3): d=6.01 (m, 1H, NH), 5.82 (m, 1H, NH), 4.80–4.72 (m, 2H,
CH), 4.67 (dd, J=8.6/4.2 Hz, 1H, CH), 4.62 (dd, J=8.7/4.4 Hz, 1H, CH),
4.43 (m, 1H, CH), 4.32–4.25 (m, 4H, 2ꢃCH2), 3.92–3.88 (m, 4H, 2ꢃ
CH2), 3.81 (m, 1H, CH), 3.72 (m, 1H, CH), 3.68 (s, 3H, OCH3), 3.64 (s,
3H, OCH3), 3.45 (m, 1H, CH), 3.34 (t, J=10.9 Hz, 1H, CH), 1.43 (s, 9H,
(CH3)2C), 1.42 (s, 9H, (CH3)2C), 0.97 (d, J=6.4 Hz, 3H, H-21), 0.92 (s,
3H, H-19), 0.83 (s, 3H, H-18), 0.79 ppm (d, 3H, J=6.3 Hz, H-27);
13C NMR (100 MHz, CDCl3): d=174.2, 174.0, 170.5, 170.2, 170.1, 169.7,
168.8, 168.7, 154.9, 154.6, 109.4, 80.9, 80.4, 80.2, 71.4, 70.8, 66.6, 62.2, 61.8,
61.6, 59.4, 59.3, 56.0, 54.4, 53.6, 53.5, 52.7, 52.6, 49.8, 47.7, 47.6, 43.8, 42.8,
41.7, 40.7, 40.1, 39.6, 38.6, 35.6, 35.0, 31.7, 31.4, 31.2, 30.1, 30.0, 28.8, 28.5,
28.3, 28.1, 19.2, 17.1, 16.7, 14.5, 13.8 ppm; IR (KBr): n˜ =3446, 3381, 2930,
2871, 1998, 1677, 1664, 1651, 1455, 1366, 1240, 1170, 1053, 979, 919, 899,
865 cmꢀ1; HRMS (ESI-FT-ICR): m/z calcd for C55H90NaN6O4: 1113.6317;
found: 1113.6324 [M+Na]+.
1211, 1168 cmꢀ1; HRMS (ESI-FT-ICR): m/z calcd for C60H78NaO18N10
1249.5396; found: 1249.5395 [M+Na]+.
:
Podand 11: Triisonitrile 6 (88 mg, 0.5 mmol), paraformaldehyde (45 mg,
1.5 mmol), isopropylamine (0.13 mL, 1.5 mmol), and cholic acid
9
(610 mg, 1.5 mmol) were reacted according to the general threefold Ugi-
4CR-based procedure. Flash column chromatography purification
(CH2Cl2/MeOH 5:1) afforded podand 11 (492 mg, 61%) as a white solid.
M.p. (from MeOH): 263–2668C; 1H NMR (400 MHz, CD3OD): d=4.26–
4.22 (m, 3H), 4.12–4.06 (m, 6H, 3ꢃCH2), 3.96 (m, 3H, 3ꢃCH), 3.79 (m,
3H, 3ꢃCH), 3.36 (m, 3H, 3ꢃCH), 3.25–3.20 (m, 6H, 3ꢃCH2), 1.28–1.22
(m, 18H, 3ꢃ(CH3)2CH), 1.00 (s, 9H, 3ꢃCH3), 0.91 (m, 9H, 3ꢃCH3),
0.71 ppm (m, 9H, 3ꢃCH3); 13C NMR (100 MHz, CD3OD): d=170.2,
169.8, 169.4, 71.8, 69.1, 68.7, 56.4, 52.3, 51.4, 48.9, 47.8, 44.6, 42.7, 42.0,
40.3, 40.1, 39.8, 36.4, 35.8, 35.3, 34.5, 33.0, 31.3, 30.5, 28.7, 27.1, 26.3, 24.1,
23.3, 20.7, 18.6, 12.1 ppm; IR (KBr): n˜ =3420, 3365, 2935, 2868, 1684,
1667, 1656, 1622, 1463, 1444, 1251, 1193, 1073, 1044 cmꢀ1; HRMS (ESI-
FT-ICR): m/z calcd for C93H159O15N7: 1614.1801; found: 1614.1786
[M+H]+.
Spirostanic peptide–peptoid hybrid 33: Diisocyanide 23 (225 mg,
0.5 mmol), paraformaldehyde (30 mg, 1.0 mmol), isopropylamine
(0.09 mL, 1.0 mmol), and N-Cbz-l-proline (249 mg, 1.0 mmol) were react-
ed according to the general polyfold Ugi-4CR-based procedure. Flash
column chromatography purification (CH2Cl2/MeOH 18:1) afforded 33
Podand 12: Triisonitrile 6 (88 mg, 0.5 mmol), paraformaldehyde (45 mg,
1.5 mmol), cholanyl amine 10 (635 mg, 1.5 mmol) and acetic acid
(0.09 mL, 1.5 mmol) were reacted according to the general threefold Ugi-
4CR-based procedure. Flash column chromatography purification
(CH2Cl2/MeOH 5:1) afforded podand 12 (263 mg, 32%) as a white solid.
M.p. (from MeOH): 298–3018C; 1H NMR (400 MHz, CD3OD): d=4.02–
3.98 (m, 6H, 3ꢃCH2), 3.92 (m, 3H, 3ꢃCH), 3.83 (m, 3H, 3ꢃCH), 3.59
(s, 9H, 3ꢃCH3O), 3.51 (m, 3H, 3ꢃCH), 3.31–3.24 (m, 6H, 3ꢃCH2), 2.08
(s, 9H, 3ꢃCH3), 0.97 (s, 9H, 3ꢃCH3), 0.92 (m, 9H, 3ꢃCH3), 0.68 ppm (s,
9H, 3ꢃCH3). 13C NMR (100 MHz, CD3OD): d=174.3, 169.8, 169.1, 70.2,
69.4, 67.3, 54.7, 52.8, 50.2, 47.6, 47.0, 45.2, 44.5, 42.4, 42.2, 40.8, 39.6, 36.2,
35.7, 35.5, 34.5, 33.2, 31.0, 30.7, 26.8, 24.0, 23.1, 21.8, 19.6, 18.2, 12.6 ppm;
IR (KBr): n˜ =3377, 3355, 2939, 2892, 1741, 1734, 1732, 1692, 1671, 1654,
1454, 1432, 1248, 1073, 1065, 1044 cmꢀ1; HRMS (ESI-FT-ICR): m/z:
calcd for C92H151O18N7: 1642.1114; found: 1642.1116 [M+H]+.
(480 mg, 88%) as
a white solid. M.p. (from MeOH): 147–1498C;
1H NMR (400 MHz, CDCl3): d=7.35–7.29 (m, 10H, 2ꢃPh), 5.86 (m, 1H,
NH), 5.68 (m, 1H, NH), 5.23–5.17 (m, 2H, CH2), 5.03–4.95 (m, 2H,
CH2), 4.78–4.74 (m, 1H, CH), 4.71–4.66 (m, 1H, CH), 4.59 (m, 1H, CH),
4.54 (m, 1H, CH), 4.34 (m, 1H, CH), 4.30–4.19 (m, 2H, CH2), 4.04–3.98
(m, 2H, CH2), 3.90 (m, 1H, CH), 3.79–3.68 (m, 3H), 3.65–3.55 (m, 2H),
3.43 (m, 1H, CH), 3.32 (t, J=10.6 Hz, 1H, CH), 1.25 (d, 6H, J=6.4 Hz,
(CH3)2CH), 1.15 (d, J=6.4 Hz, 6H, (CH3)2CH), 0.94 (d, J=6.7 Hz, 3H,
H-21), 0.81 (s, 3H, H-19), 0.77 (d, J=6.2 Hz, 3H, H-27), 0.68 ppm (s, 3H,
H-18); 13C NMR (100 MHz, CDCl3): d=172.8, 172.6, 169.4, 168.6, 154.7,
154.6, 136.5, 136.4, 128.4, 128.3, 127.9, 127.8, 127.6, 127.4, 109.3, 80.4,
77.2, 66.9, 66.7, 59.9, 57.1, 56.9, 56.8, 56.6, 55.6, 53.4, 49.0, 48.8, 46.7, 45.8,
45.4, 45.1, 42.3, 40.7, 36.2, 36.1, 33.9, 33.0, 32.3, 31.9, 31.8, 31.4, 30.2, 30.0,
29.9, 28.9, 28.3, 27.4, 25.5, 24.9, 24.7, 22.7, 21.1, 20.8, 19.7, 17.2, 13.5, 11.9,
11.3 ppm; IR (KBr): n˜ =3446, 3063, 2928, 2874, 1705, 1692, 1664, 1658,
1459, 1425, 1179, 981, 899, 765 cmꢀ1. HRMS (ESI-FT-ICR): m/z calcd for
C63H91N6O10: 1191.6794; found: 1191.6799 [M+H]+.
Podand 14: CTV-based triacid 13 (653 mg, 0.5 mmol, dissolved in 10 mL
of H2O), paraformaldehyde (45 mg, 1.5 mmol), isopropylamine (0.13 mL,
1.5 mmol) and benzylisocyanide (0.14 mL, 1.5 mmol) were reacted ac-
cording to the general threefold Ugi-4CR-based procedure. Flash column
chromatography purification (CH2Cl2/MeOH 15:1) afforded podand 14
Furostanic peptide–peptoid hybrid 34: Diisocyanide 25 (247 mg,
0.5 mmol), paraformaldehyde (30 mg, 1.0 mmol), N-Boc-l-cysteine
(221 mg, 1.0 mmol), l-alanine methyl ester hydrochloride (139 mg,
1.0 mmol) and Et3N (0.14 mL, 1.0 mmol) were reacted according to the
general polyfold Ugi-4CR-based procedure. Flash column chromatogra-
phy purification (CH2Cl2/MeOH 15:1) afforded 34 (426 mg, 73%) as a
white solid. M.p. (from EtOAc): 165–1678C; 1H NMR (400 MHz,
CDCl3): d=7.38 (m, 2H, 2ꢃNH), 5.29 (m, 2H, 2ꢃNH), 4.58–4.53 (m,
2H, 2ꢃCH), 4.33–4.28 (m, 3H), 4.24–4.19 (m, 4H, 2ꢃCH2), 3.97–3.90
(m, 2H), 3.82 (m, 1H, CH), 3.73 (m, 1H, CH), 3.76, 3.73 (2 s, 6H, 2ꢃ
CH3O), 3.52–3.44 (m, 2H, CH), 3.32 (m, 1H, CH), 2.82–2.77 (m, 4H, 2ꢃ
CH2), 2.02 (s, 1H, CH3CO), 1.61–1.55 (m, 2H), 1.47 (d, J=7.2 Hz, 3H,
CH3), 1.45 (d, J=7.2 Hz, 3H, CH3), 1.42, 1.40 (2 s, 18H, 2ꢃ(CH3)3C),
(338 mg, 59%) as
a white solid. M.p. (from EtOAc): 221–2238C;
1H NMR (400 MHz, CDCl3): d=7.13 (m, 15H, 3ꢃPh), 6.82 (m, 3H, Ar),
6.75 (m, 3H, Ar), 4.70 (m, 3H), 4.64 (m, 6H, 3ꢃCH2), 4.57–4.50 (m, 6H,
3ꢃCH2), 4.26–4.21 (m, 6H, 3ꢃCH2), 4.15–4.09 (m, 3H, 3ꢃCH), 3.80 (s,
9H, 3ꢃOCH3), 3.72 (s, 9H, 3ꢃOCH3), 3.59 (m, 3H), 1.07–1.01 ppm (m,
18H, 3ꢃ(CH3)2CH); 13C NMR (100 MHz, CDCl3): d=169.1, 169.0, 148.0,
145.4, 138.0, 133.8, 131.2, 128.1, 127.3, 127.0, 126.8, 116.4, 113.5, 69.0,
58.4, 55.7, 48.7, 42.6, 36.0, 30.7, 23.5, 20.7, 19.4, 13.4 ppm; HRMS (ESI-
FT-ICR): m/z calcd for C66H78NaO12N6: 1169.5569; found: 1169.5556
[M+Na]+.
Podand 16: Kempꢂs triacid 15 (129 mg, 0.5 mmol), paraformaldehyde
(45 mg, 1.5 mmol), (0.13 mL, 3.0 mmol) and benzylisocyanide (0.14 mL,
6426
www.chemeurj.org
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 6417 – 6428

Chimeric Peptide–Peptoid Podands
FULL PAPER
0.98 (d, J=6.6 Hz, 3H, CH3), 0.91 (d, J=6.5 Hz, 3H, CH3), 0.84 (s, 3H,
CH3), 0.80 ppm (s, 3H, CH3); 13C NMR (100 MHz, CDCl3): d=172.0,
171.4, 171.2, 170.4, 167.8, 167.5, 154.9, 154.8, 90.4, 80.0, 79.9, 83.3, 78.9,
78.8, 69.9, 56.5, 56.7, 56.0, 54.5, 52.6, 52.5, 52.3, 52.0, 51.5, 51.3, 51.0, 50.9,
50.0, 47.9, 46.8, 42.2, 39.4, 39.1, 38.1, 37.0, 35.7, 32.2, 32.0, 31.5, 30.4, 30.2,
28.6, 28.5, 28.45, 28.4, 28.3, 21.3, 20.6, 18.8, 18.3, 16.5, 16.4 ppm; IR
(KBr): n˜ =3437, 3389, 2939, 2865, 1724, 1685, 1676, 1669, 1654, 1457,
1369, 1034 cmꢀ1; HRMS (ESI-FT-ICR): m/z calcd for C57H94N6NaO15S2:
1189.6120; found: 1189.6116 [M+Na]+.
127.8, 77.2, 74.4, 67.0, 66.8, 51.5, 50.9, 49.4, 49.0, 48.4, 46.4, 44.6, 44.3,
43.9, 41.1, 36.9, 35.2, 35.0, 34.9, 32.1, 31.3, 30.8, 29.5, 28.6, 27.3, 26.4, 25.6,
23.3, 22.8, 21.8, 21.8, 21.7, 21.5, 20.4, 20.3, 17.2, 13.2 ppm; IR (KBr) n˜ =
3411, 3065, 3033, 2939, 2871, 1727, 1655, 1583, 1451, 1247, 1050,
1027 cmꢀ1; HRMS (ESI-FT-ICR): m/z calcd for C65H91N10O12: 1203.6812;
found: 1202.6812 [M+H]+.
Cholanic peptide–peptoid hybrid 35: Trisocyanide 27 (232 mg, 0.5 mmol),
paraformaldehyde (45 mg, 1.5 mmol), isopropylamine (0.13 mL,
1.5 mmol), and Na-Boc-l-tryptophan (456 mg, 1.5 mmol) were reacted ac-
cording to the general threefold Ugi-4CR-based procedure. Flash column
chromatography purification (CH2Cl2/MeOH 20:1) afforded 35 (564 mg,
Acknowledgements
We gratefully acknowledge financial support from the Deutsche For-
schungsgemeinschaft (Grant programs: GRK-894) and Land Sachsen-
Anhalt (HWP).
71%) as
a
white solid. M.p. (from EtOAc): 194–1968C; 1H NMR
(400 MHz, CDCl3): d=8.27 (m, 1H, NH), 8.15 (m, 1H, NH), 7.67 (m,
1H, NH), 7.36–7.09 (m, 15H, 3ꢃPh), 6.97 (m, 1H, NH), 6.94 (m, 1H,
NH), 6.91 (m, 1H, NH), 5.34 (m, 1H, NH), 5.24 (m, 1H, NH), 5.07 (m,
1H, NH), 4.45–3.02 (m, 23H), 2.02 (s, 3H, CH3CO), 1.46, 1.44, 1.42 (3 s,
27H, (CH3)3C), 1.37–1.32 (m, 12H, 2ꢃ(CH3)2CH), 1.25 (m, 6H,
(CH3)2CH), 0.99 (s, 3H, H-19), 0.83 (s, 3H, H-18), 0.82 ppm (d, J=
6.2 Hz, 3H, H-21); 13C NMR (100 MHz, CDCl3): d=173.9, 173.6, 173.3,
171.5, 169.3, 168.9, 168.6, 168.4, 155.2, 155.1, 155.0, 136.2, 136.0, 127.4,
127.2, 127.0, 123.6, 124.4, 123.0, 122.1, 121.9, 121.6, 119.7, 119.4, 118.4,
117.7, 11.3, 110.3, 110.0, 80.7, 80.3, 80.0, 64.9, 53.4, 52.0, 50.7, 50.4, 40.0,
49.5, 49.3, 48.9, 48.7, 46.6, 46.4, 46.3, 45.9, 45.2, 44.3, 44.1, 37.0, 36.7, 36.5,
35.3, 35.0, 32.1, 31.9, 31.1, 30.5, 30.0, 29.6, 29.2, 28.6, 28.4, 28.3, 28.2, 28.0,
27.6, 27.4, 26.3, 25.7, 25.6, 24.6, 23.5, 23.4, 22.7, 21.7, 21.5, 21.0, 20.7, 20.3,
19.7, 19.4, 17.7, 14.1, 13.2 ppm; IR (KBr): n˜ =3427, 3092, 3031, 2970,
1724, 1669, 1654, 1543, 1451, 1229, 1172, 1031 cmꢀ1; HRMS (ESI-FT-
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ICR): m/z calcd for C89H128NaN12O14
[M+Na]+.
: 1611.9550; found: 1611.9539
Cholanic peptide–peptoid hybrid 36: Diisocyanide 29 (241 mg,
0.5 mmol), paraformaldehyde (30 mg, 1.0 mmol), isopropylamine
(0.09 mL, 1.0 mmol), and N-Boc-l-phenylalanine (275 mg, 1.0 mmol)
were reacted according to the general polyfold Ugi-4CR-based proce-
dure. Flash column chromatography purification (CH2Cl2/MeOH 20:1)
afforded 36 (474 mg, 82%) as a white solid. M.p. (from CH2Cl2/n-
1
hexane): 134–1368C. H NMR (400 MHz, CDCl3): d=7.29–7.18 (m, 10H,
2ꢃPh), 6.97 (m, 1H, NH), 6.37 (m, 1H, NH), 6.08 (m, 1H, NH), 5.86 (m,
1H, NH), 4.99 (m, 1H, CH), 4.40–4.34 (m, 2H), 4.27–4.15 (m, 4H), 3.81–
3.79 (m, 2H), 3.73 (m, 1H, CH), 3.65 (s, 3H, OCH3), 3.59 (m, 1H, CH),
2.01 (s, 3H, CH3CO), 1.40 (s, 9H, (CH3)3C), 1.37 (s, 9H, (CH3)3C), 1.26–
1.22 (m, 12H, (CH3)2CH), 0.96 (s, 3H, H-19), 0.85 (d, 3H, J=5.6 Hz, H-
21), 0.80 ppm (s, 3H, H-18); 13C NMR (100 MHz, CDCl3): d=174.3,
173.2, 172.7, 172.6, 171.0, 170.4, 169.0, 168.8, 168.2, 155.0, 154.8, 136.5,
136.3, 136.1, 135.7, 129.1, 128.5, 128.4, 127.0, 126.8, 80.4, 80.0, 76.2, 74.6,
71.3, 70.8, 60.4, 51.8, 51.5, 51.2, 49.5, 49.3, 48.5, 48.3, 46.3, 45.9, 45.8, 44.7,
44.5, 44.3, 41.4, 40.9, 40.0, 39.6, 36.9, 35.3, 35.0, 34.8, 34.6, 31.8, 31.4, 31.0,
30.6, 28.5, 28.4, 28.3, 27.5, 26.9, 26.3, 23.3, 23.0, 22.7, 21.7, 21.6, 20.7, 20.3,
17.2, 14.3, 13.5 ppm; IR (KBr): n˜ =3433, 3085, 3026, 2972, 2937, 1735,
1712, 1680, 1521, 1453, 1367, 1247, 1170, 1027 cmꢀ1; HRMS (ESI-FT-
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ICR): m/z calcd for C65H98NaN6O12
[M+Na]+.
: 1177.7135; found: 1177.7150
Cholanic peptide–peptoid hybrid 37: Diisocyanide 31 (241 mg, 0.5 mmol),
paraformaldehyde (30 mg, 1.0 mmol), isopropylamine (0.09 mL,
1.0 mmol), and N-Cbz-l-histidine (289 mg, 1.0 mmol) were reacted ac-
cording to the general polyfold Ugi-4CR-based procedure. Flash column
chromatography purification (CH2Cl2/MeOH 15:1) afforded 37 (463 mg,
77%) as
a
white solid. M.p. (from EtOAc): 139–1408C; 1H NMR
(400 MHz, CDCl3): d=7.47 (m, 2H, 2ꢃCH-imid.), 7.31 (m, 5H, Ph), 7.29
(m, 5H, Ph), 6.74 (m, 2H, 2ꢃCH-imid.), 5.89 (m, 1H, NH), 5.08 (m, 2H,
CH2), 5.04 (s, 2H, CH2), 4.87–4.84 (m, 2H), 4.54 (brm, 1H, CH), 4.23–
4.19 (m, 2H, CH2), 4.15–4.10 (m, 2H, CH2), 3.84 (m, 1H, CH), 3.62 (m,
1H, CH), 3.59 (s, 3H, OCH3), 1.18 (d, J=6.6 Hz, 6H, (CH3)2CH), 1.14
(d, J=6.6 Hz, 6H, (CH3)2CH), 0.97 (s, 3H, H-19), 0.81 (d, J=6.0 Hz, 3H,
H-21), 0.78 ppm (s, 3H, H-18); 13C NMR (100 MHz, CDCl3): d=174.4,
170.4, 172.6, 171.7, 170.4, 169.0, 155.5, 155.4, 136.0, 135.7, 128.4, 128.0,
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Revised: January 31, 2013
Published online: March 19, 2013
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