Rapid generation of macrocycles with natural-product-like side chains by multiple multicomponent macrocyclizations (MiBs)

Article abstract of DOI:10.1039/b715393g

A small parallel library of peptoid macrocycles with natural-product- derived side chains of biological importance was produced by Ugi-type multiple multicomponent macrocyclizations including bifunctional building blocks (Ugi-MiBs). Diverse exocyclic elements of high relevance in natural recognition processes, i.e., all functional amino acid residues (e.g., Cys, Arg, His, Trp) and even sugar moieties, can be introduced in a one-pot process into different types of peptoid-containing macrocyclic skeletons. This is exemplified by the use of a diamine/diisocyanide combination of Ugi-MiBs and N-protected α-amino acids or carboxy-functionalized carbohydrates as source for the natural-product-like exocyclic elements. Employed as the acid components of the multiple Ugi reactions, they appear as N-amide substituents on the macrocyclic cores. The use of different diamines and diisocyanides allows an easy variation of the N- to C-directionality and therefore of the position of the exocyclic elements. The Royal Society of Chemistry.

Full text of DOI:10.1039/b715393g

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Rapid generation of macrocycles with natural-product-like side chains by
multiple multicomponent macrocyclizations (MiBs)
Daniel G. Rivera,a,b Otilie E. Vercilloa,c and Ludger A. Wessjohann*a
Received 8th October 2007, Accepted 11th March 2008
First published as an Advance Article on the web 28th March 2008
DOI: 10.1039/b715393g
A small parallel library of peptoid macrocycles with natural-product-derived side chains of biological
importance was produced by Ugi-type multiple multicomponent macrocyclizations including
bifunctional building blocks (Ugi-MiBs). Diverse exocyclic elements of high relevance in natural
recognition processes, i.e., all functional amino acid residues (e.g., Cys, Arg, His, Trp) and even sugar
moieties, can be introduced in a one-pot process into different types of peptoid-containing macrocyclic
skeletons. This is exemplified by the use of a diamine/diisocyanide combination of Ugi-MiBs and
N-protected a-amino acids or carboxy-functionalized carbohydrates as source for the
natural-product-like exocyclic elements. Employed as the acid components of the multiple Ugi
reactions, they appear as N-amide substituents on the macrocyclic cores. The use of different diamines
and diisocyanides allows an easy variation of the N- to C-directionality and therefore of the position of
the exocyclic elements.
the positioning of the appended functionalities (i.e., side chains
Introduction
or exocyclic residues) is not only influenced by the amino acid
Natural macrocycles are increasingly important in medicinal
configuration but also by the overall conformation of the cavity.
chemistry as active principles or as lead structures for drug
In this sense, synthetic macrocyclic skeletons have been devised
discovery. Synthetic derivatives are either based on rational design
or on privileged structural elements incorporated in combinatorial
either to seek desired arrangements of exocyclic functionalities or
to impose a specific conformation on oligopeptide chains (e.g.,
libraries.1,2 Apart from the use of natural macrocyclic scaffolds,
in medicinal chemistry the cyclization of various skeletons is
widely employed with the aim to improve pharmacological
properties3 and to decrease the entropy loss upon binding.4 This is
especially relevant for cyclopeptides, wherein important properties
such as bioavailability and enzymatic stability are significantly
improved.1a,3 Cyclization is also used to introduce conformational
restrictions into specific peptide sequences that are known to
be recognized by biological receptors,3d,5,6 e.g., RGD-containing
peptides.5
b-turn mimics).11
Exocyclic elements that appear frequently in natural macro-
cycles are a-amino acid side chains, or heterocycles such as
oxazoles and thiazoles.1,2,7–9 Another group, at least as frequent
in occurrence, are exocyclic carbohydrates. Each one of these
exocyclic motifs usually displays a specific biological role. The
function of (for example) exocyclic sugar moieties in macrocycles
such as the macrolides and glycopeptide antibiotics is a topic of
great interest, as their absence leads to the partial or complete
loss of the aglycon bioactivity.8 It is well-known that the exocyclic
sugar units influence the overall recognition and transport (e.g.,
through higher water solubility) of active macrocycles,8,12 even
in cases where they do not participate in the activation at the
target protein itself. It seems also that glycosylation is part of the
mechanism of self-protection of the antibiotic-producing bacteria
towards further modifications.8b The role of the exocyclic amino
acids, their side chains as well as the 5-membered heterocycles
definitely rests on their participation in the binding to the
biological target. Overall, depending on the mode of action of
the macrocycle, the exocyclic functionalities can have a higher
(protein binding) or lower (membrane activity) importance for
the recognition process compared to the endocyclic motifs role.
Herein we report on the use of the Ugi-MiB (MiB = multiple
multicomponent macrocyclization including bifunctional building
blocks) strategy13 to generate macrocycles with exocyclic natural
product resemblance. Of the various Ugi-MiBs available, the
diamine/diisocyanide combination was chosen as it does not
generate extra exocyclic elements by itself. Thus, typical natural
macrocycle appendages can be incorporated as the acid compo-
nent. The challenge is to include such side chains, which tend to be
Natural amino acid-derived macrocycles are of special relevance
in the realm of biologically active compounds.1,7 They may be
found either as oligomeric sequences (e.g., cyclopeptides and
depsipeptides) or as hybrid skeletons including diverse endocyclic
chemical motifs alternating with the peptide sequences. Well-
known moieties include the biarylether unit,1e,k,8 5,6-membered
heterocycles (e.g., oxazole and thiazole)1e,9 or lipophilic chains
(e.g., polyene and phenylene).1e,2a,10 While endocyclic motifs are
known to be important for conformational constrains, rigidity and
shape, biological and structural studies have shown that exocyclic
elements are relevant for the overall biological profile, such as the
recognition and functional elements of macrocycles.1,2,5,6 This is
especially noteworthy in amino acid-derived macrocycles wherein
aDepartment of Bioorganic Chemistry, Leibniz Institute of Plant Biochem-
istry, Weinberg 3, D-06120, Halle/Saale, Germany. E-mail: wessjohann@
ipb-halle.de; Fax: +49 345 5582 1309; Tel: +49 345 5582 1301
bCenter for Natural Product Studies, Faculty of Chemistry, University of
Havana, 10400, Havana, Cuba
cLaborato´rio de Qu´ımica Metodolo´gica e Orgaˆnica Sinte´tica, Instituto de
Qu´ımica, Universidade de Bras´ılia, CP 4478, 70910-970, Bras´ılia DF, Brasil
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problematic in the Ugi four-component reaction (Ugi-4CR), but
which are at the same time of dominant biological importance as
they bear specific recognition elements, e.g., amino, carboxylate,
guanidinium, imidazole groups, etc.
favours a faster completion of the Ugi-4CRs. Similar experiments,
wherein the diamine was also slowly added to a solution of
paraformaldehyde, were less successful despite the higher dilution
of each bifunctional building block. This confirms the advantage
of performing the imine-condensation prior to the addition of
the other components, a process that is fairly slow at least with
paraformaldehyde. Another practical issue to be optimized was
the flow rate of addition of the diisocyanide via syringe pump.
The aim was to achieve a compromise between good yields
and short reaction times. Thus, the optimized protocol, which
involves reaction times of ca. 30 hours, leads to isolated total
yields ranging from ca. 40 to 50%. Under these conditions, small
amounts of acyclic oligomers were sometimes detected by ESI-
MS analysis, though they were significantly more polar than the
cyclized compounds and easy to separate. Slower addition rates
increased the macrocycle yields, but for significant improvements
the reaction times required are too long (i.e., several days or weeks)
and therefore unsuitable to create macrocycle libraries.
One of the main goals of this study was to explore which a-amino
acids could be employed as the acid components in Ugi-MiBs, and
if they needed side chain protection or not. Priority was given to
natural building blocks possessing recognized binding capabilities
derived from the functional groups present in their side chains. The
set of a-amino acids shown in Scheme 1 demonstrates that many
biologically relevant functional side chains (i.e., those of serine,
histidine, glutamine, and cysteine) do not require protection when
the amino acid is employed as the acid component in an Ugi-
MiB. Of course, Ugi-reactive groups, such as amino groups at the
a-position or in the side chain (as in lysine), or any other carboxylic
acid group present (as in aspartic and glutamic acid), must be
protected to avoid their uncontrolled participation in the Ugi-MiB.
The successful conversion of unprotected cysteine as the acid
component is unexpected, as its alternative use as the amino
component (i.e., in the C-protected form) in the Ugi-4CR is
completely ineffective. This latter case is known to be due to the
inactivation of the pre-formed imine by formation of a thiazolidine
derivative. As the disulfide exchange is a highly useful process for
conjugation and in dynamic combinatorial chemistry, this example
can be considered as an interesting entry to future applications
based on disulfide exchange.
Results and discussion
The Ugi-MiB approach, i.e. a MiB based on multiple Ugi-
4CRs, is a versatile strategy towards the rapid creation of
macrocycle libraries. It encompasses the use of two building blocks
bifunctionalized with Ugi-reactive groups which are allowed
to undergo a cyclodimerization process in the presence of the
other monofunctional Ugi-components. The resulting scaffolds
are macrocycles containing two peptoid moieties and assembled
through the formation of 8 new bonds in one pot.13 Peptoids
(i.e., N-substituted oligoglycines) are an interesting family of
peptidomimetics exhibiting a wide variety of biological activities
and often improved pharmacological properties over peptides,
such as better bioavailability.14 Peptoid backbones previously have
been incorporated into steroid-based macrocycles and cryptand-
type skeletons with the aim of evaluating their molecular and ion
pair recognition capabilities.13a,15
Recently, the creation of parallel and combinatorial libraries of
natural-like macrocycles by Ugi-MiBs has been reported.16 This
issue seems to be especially promising as the method relies on the
unification of both cyclization and amide N-substitution in order
to seek biologically active peptoid-containing macrocycles. These
previous studies have focused on structural requirements (e.g.,
length, flexibility) of the endocyclic moieties essential to achieve
a successful double Ugi-4CR-based macrocyclization.13,16 This
article aims to reveal which natural exocyclic elements can be in-
corporated in a reliable manner by using the diamine/diisocyanide
combination of Ugi-MiB, thus addressing one of the many
diversity elements that can be varied in one pot.
Initial efforts on the synthesis of natural-product-inspired
macrocycles were directed at the incorporation of a biarylether
moiety as the endocyclic element.16a,b It was shown that diamines
that were either too rigid or too short were unable to undergo
the ring closure when used as counterparts of the rigid aryl-based
diisocyanides (e.g., 6).16a,b Accordingly, it was decided to employ
long and more-or-less flexible diamines as counterparts of the
previously described diisocyanides 1 and 6. The use of hetero-
functionalized diamines was preferred to aliphatic ones, as the
latter not only give lower yields but also are unable to act as
binding motifs or control elements, e.g., with metal ions.
Scheme 1 shows the first examples of the creation of natural-
product-derived exocyclic appendages based on the use of N-
protected a-amino acids as the acid components. Paraformalde-
hyde was always employed as the oxo component to avoid the
formation of stereoisomers. The resemblance of these compounds
to macrocyclic natural products perfectly illustrates the potential
of the method to create libraries amenable to biological screening.
As usual in macrocyclization approaches, experiments were
carried out under pseudo-high-dilution conditions. These con-
sisted in the slow addition of the diisocyanide to a stirring
mixture of the other components, i.e., the acid and the diimine
formed from the diamine and paraformaldehyde. Although this
protocol does not ensure high dilution of the diamino building
block, the pre-formation of the corresponding iminium species
However, our investigation afforded undesired results with
regard to other a-amino acid side chains that can interfere with the
normal course of the double Ugi-4CR-based macrocyclization.
For example, the use of tri-protected arginines (viz., Na,Nd,Nx-
tri-Boc-L-arginine and tri-Cbz-L-arginine), was completely inef-
fective. No Ugi-product, cyclic or otherwise, could be identified in
the reaction crude of the guanidinium carbamates. Considering the
mechanism of the Ugi four-component reaction, this failure may
have two different reasons:13b,17 i) the impossibility of the “normal”
a-adduct to be formed, or ii) the deviation of the normal Mumm
rearrangement by an intramolecular acylation of the guanidinium
instead of the nitrogen of the former Ugi-amino component. This
secondchoiceseems tobe more plausible as the a-adduct is a strong
acylating agent17 and the guanidinium group is a nucleophile, even
if protected as the carbamate.
The dominant role of guanidinium groups in many molecular
recognition processes of biological relevance required the search
for a suitable protection that allows their reliable incorporation
into macrocycles via the Ugi-MiB. Eventually, it was found
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Scheme 1 Ugi-MiB approach towards natural-product-like macrocycles with appended a-amino acids (Ser, His, Cys, Gln).
that protection with 2,4-dimethoxybenzyl (Dmb) and 2,2,5,7,8-
pentamethylchromane-6-sulfonyl (pmc) at the nucleophilic centers
does not affect the normal course of an Ugi-4CR.18
procedure of formylation and dehydration for aliphatic amines21
gave the diisocyanides on a multi-gram scale. Scheme 3 illustrates
their use in combination with suitably protected tryptophane and
glutamic acid, as well as a guanidinium and a carbohydrate-
containing building block.
Macrocycle 19 illustrates access to arginine-like side chains by
application of N-protected d-guanidinium butyric acid 13. The
employed protecting groups are also suitable to introduce natural
arginine itself, as this amino acid is known to be accessible from
ornithine by the same guanylation approach.19
Macrocycles 19 and 20 were also designed to exemplify the
easy fine-tuning of the positioning of the exocyclic elements
derived by variation of the peptoid N- to C-terminal directionality.
The two compounds were obtained from the same type of
bifunctional building block core as macrocycles 5 and 3 (cf.
Scheme 1 vs. Scheme 3), respectively, but with the Ugi-reactive
functional groups interchanged between the building blocks. This
As depicted in Scheme 2, a short and practical route was em-
ployed to synthesize the guanidinium-containing building block
13 from amino acid 9. This includes the protection with Dmb of the
primary amine followed by formation of the guanidinium group
utilizing 1H-pyrazole-1-carboxamidine 11 as the guanylating
reagent.19 This pmc-protected reactant (11) has been previously
described for the guanylation of amines,20 and proved equally
suitable for the synthesis of compound 12 in 76% overall yield
from 9. Finally, methyl ester cleavage under mild conditions
afforded acid 13, which was employed in the double Ugi-4CR-
based macrocyclization without further purification.
Scheme 2 shows the syntheses of diisocyanides 15, 16, and 17
from commercially available diamino building blocks to enhance
the diversity of Ugi-MiB libraries. The straightforward standard
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Scheme 2 Synthesis of mono- and bifunctional building blocks for Ugi-MiBs.
was possible by using diamine 18 (the precursor of diisocyanide
1) as the counterpart of diisocyanides 16 and 17 (arising from
diamines 2 and 4), thus resulting in macrocycles having the
same size, hybridization and functional groups, but in a different
orientation and with the appended functionalities attached at
different positions. This idea can be used to more rapidly access
QSARs of bioactive compounds, as the fine-tuning of the positions
of the side chains is available with only very few synthetically
related building blocks.
The lower yield of compound 24 (35%) compared to the earlier
macrocycles is not a result of the sugar moiety used. The ring
closure step in smaller macrocycles is more problematic with
two aryl bifunctional building blocks forming a cyclophane.
This was proven by further synthetic studies utilizing the same
bifunctional building blocks and simpler acid components under
the same pseudo-high-dilution conditions. With the rigid arylene
moieties, conditions that are suitable for more flexible diamines
now did result in the formation of large amounts of acyclic
products. Interestingly, when p-xylylenediamine (18) was used as
the counterpart of diisocyanide 6, no macrocyclic product could
be obtained. This supports previous reports from our laboratory
concerning the endocyclic structural requirements needed to
succeed with Ugi-MiBs for the assembly of peptoid-containing
macrocycles.13a,16
The NMR analysis of the macrocycles obtained suggests the
existence of various conformers at room temperature. This is
typical for peptoid-based compounds, as the N-alkylation of the
amide bond reduces the energy barrier between the s-cis and the
s-trans configuration, thus allowing easier isomerization. The fact
that the appended functional side chains are directly attached
to the N-substituted amide and not at the a-carbon as in other
cyclopeptides may be seen as a unifying concept of the approach
presented here. With respect to skeletal mobility, peptoids as
(cyclic) peptide mimics are related to N-methyl (cyclo)peptides. A
recent literature survey revealed that in biologically active macro-
cycles, methylation is the most common N-alkylation reaction
used by nature (as well as by medicinal chemists) in order to
address physiological stability, lipophilicity, and conformational
changes based on amide bond isomerization.1a However, an
intentional relocation of exocyclic elements with natural binding
capabilities to substitute N-methylation and side chain at the same
time has not yet been explored in detail.
The synthesis of macrocycle 22 highlights the use of natural
amino acids not only as exocyclic elements, but here also as part
of the endocyclic framework.
The last part of this work deals with the one-pot incorporation
of carbohydrate moieties as exocyclic elements of macrocycles.
Typical sugar units found in natural macrocycles can have
deoxy centers, methyl, or amino or carboxylate substituents
along with residual hydroxy groups.8,12 This feature provides a
mixed hydrophilic/hydrophobic nature that seems to be crucial
in the delivery and/or recognition of the natural product to
the biological target. The incorporation of these natural sugar
moieties has been described as a great challenge in total synthesis.1k
Therefore, rather than devoting much effort to the synthesis of such
carbohydrates, our aim is simply to illustrate the possibility of
incorporating amino-sugars as exocyclic elements of natural-like
macrocycles. To accomplish this, they need to be functionalized
with any of the Ugi-reactive groups. To remain in the context of
this paper, the protected amino-glucose (GlcN)-derived carboxylic
acid 23 was used along with the biaryl ether diisocyanide 6 and
diamine 14 in the synthesis of macrocycle 24. Considering that
carbohydrates have been employed as any of the four components
of an Ugi-4CR in acyclic systems,22 their use in the MiB strategy
may be devised also for any of the six other principal combinations
of Ugi-MiBs.13
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Scheme 3 Ugi-MiB approach towards natural-like macrocycles with appended a-amino acids (Glu, Trp), guanidinium groups (Arg-mimic), and sugar
(GlcN) moieties.
This type of macrocycle, available by the MiB method or similar
approaches,1a,5f ,13–16 is expected to combine the pharmacological
advantages of cyclopeptides and peptoids (i.e., improved bioavail-
ability and physiological stability) in a single structure. Addition-
ally, the occurrence of various low-energy conformations of these
macrocyclic frameworks comprises the generation, and therefore
screening, of a larger conformational space of exocyclic function-
alities compared to those accessible by locating the side chain at
an a-carbon atom with predefined stereochemistry. Finally, it must
be mentioned that this method is not restricted to macrocycles
including N-substituted glycines; prochiral oxo-compounds can
also be employed with similar success. This gives rise to an even
larger chemical space, including all possible stereoisomers.
blocks and the incorporation of natural-product-type side chains
as acid components of the Ugi-4CR-based macrocyclizations.
The study proved that, with the exception of arginine, all other
proteinogenic amino acids containing functional side chains can
be introduced as exocyclic elements in one pot. The only structural
requirement is that any amino or carboxy functionality that
is desired in addition to the reacting functionality, must be
protected during the macrocyclization. A solution for the incor-
poration of arginine-like moieties required a special combination
of guanidinium protective groups. Finally, a promising route to
the straightforward incorporation of carbohydrate moieties as
appended functionalities of macrocycles has been presented.
Experimental
Conclusions
Melting points were determined on a Leica DM LS2 apparatus
and are uncorrected. 1H NMR and 13C NMR spectra were
recorded on a Varian Mercury 300 spectrometer at 300.2 MHz
and 75.5 MHz, respectively. Chemical shifts (d) are reported in
ppm relative to TMS (1H NMR) and to the solvent signal (13C
The Ugi-MiB strategy proved suitable for the rapid and efficient
generation of diverse macrocycles with exocyclic substituents
resembling (cyclopeptide) natural products. This was exemplified
by the diamino/diisocyanide combination of bifunctional building
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NMR). IR spectra were obtained on a Bruker FT-IR spectrometer.
High resolution ESI mass spectra were obtained from a Bruker
Apex III Fourier transform ion cyclotron resonance (FT-ICR)
mass spectrometer equipped with an InfinityTM 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 lm,
1 × 100 mm column, flow 70 ll min−1. Flash column chromatog-
raphy 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 aluminium sheets. The solid com-
pounds were recrystallized from selected solvents for the melting
point measurements. All commercially available chemicals were
used without further purification unless stated differently. Diiso-
cyanides 1 and 6 were obtained as described in refs. 15 and 16. Acid
23 was prepared according to the procedure described in ref. 22a.
1540, 1249, 1166. 1H NMR (CDCl3): d = 7.51 (s, 2H, CH-imid.);
7.28 (s, 4H, CH-Ph); 6.82 (s, 1H, CH-imid.); 6.79 (s, 1H, CH-
imid.); 5.49–5.46 (m, 2H, NH); 4.69–4.66 (m, 2H, CH); 4.26–4.16
(m, 4H, CH2); 3.61–3.56 (m, 4H, CH2); 3.39 (m, 4H, CH2); 3.33–
3.31 (m, 4H, CH2); 3.24–3.20 (m, 4H, CH2); 3.11 (m, 2H, CH2);
3.06 (m, 2H, CH2); 2.96 (dd, 4H, J= 14.4/4.3 Hz, CH2); 1.43 (s,
18H, (CH3)3C). 13C NMR (CDCl3): d = 172.9, 169.0, 155.0, 138.4,
135.6, 128.2, 128.1, 80.2, 77.4, 69.8, 68.3, 58.2, 53.1, 51.4, 50.7,
48.7, 42.8, 28.4. HRMS (ESI-FT-ICR) m/z: 839.4424 [M + H]+;
calcd. for C40H59O10N10: 839.4410.
Macrocycle 7
Diisocyanide 6 (110 mg, 0.5 mmol), diamine 4 (74 mg, 0.5 mmol),
paraformaldehyde (30 mg, 1 mmol), and N-Boc-L-cysteine
(221 mg, 1 mmol) were reacted according to the general macro-
cyclization procedure. Flash column chromatography purification
(CH2Cl2–MeOH 15 : 1) afforded the macrocycle 7 (167 mg, 40%)
as a white solid. Rf = 0.43 (CH2Cl2–MeOH 5 : 1). m.p. (from
EtOAc–heptane): 183–186 ◦C. IR (KBr): 3322, 3058, 2971, 1694,
General procedure for the double Ugi-4CR-based
macrocyclizations
1
1691, 1641, 1463, 1234, 1209, 1171. H NMR (CDCl3): d = 9.38
A solution of the diamine (0.5 mmol) and paraformaldehyde
(1.0 mmol) in MeOH (150 mL) was stirred for 2 h at room
temperature. The acid (1.0 mmol) was then added and the stirring
continued for 30 min. A solution of the diisocyanide (0.5 mmol)
in MeOH (20 mL) was slowly added to the reaction mixture
using a syringe pump (flow rate 0.5 mL h−1). After addition
was completed, the reaction mixture was stirred for 8 h and
concentrated under reduced pressure to give a crude product,
which was purified by flash column chromatography.
(br. s, 2H, NH); 9.12 (br. s, 2H, NH); 7.63 (d, 2H, J = 8.8 Hz, m-
PhNH); 7.54 (d, 2H, J= 8.9 Hz, m-PhNH); 6.97 (d, 2H, J = 9.0 Hz,
o-PhNH); 6.89 (d, 2H, J = 9.0 Hz, o-PhNH); 5.21 (br. s, 2H, NH);
4.51–4.46 (m, 4H, CH2); 4.22–4.06 (m, 4H, CH2); 3.78–3.75 (m,
4H, CH2); 3.53–3.49 (m, 4H, CH2); 3.76–3.74 (m, 4H, CH2); 1.44
(s, 18H, (CH3)3C). 13C NMR (CDCl3): d = 173.0, 172.4, 168.3,
166.9, 156.1, 133.6, 133.3, 121.2, 120.6, 119.8, 119.5, 80.8, 70.3,
63.5, 54.2, 53.2, 51.8, 51.4, 47.7, 31.4, 28.8, 28.4, 28.1. HRMS (ESI-
FT-ICR) m/z:857.3187 [M + Na]+; calcd. for C38H54NaO11N6S2:
857.3183.
Macrocycle 3
Diisocyanide 1 (78 mg, 0.5 mmol), diamine 2 (100 mg, 0.5 mmol),
paraformaldehyde (30 mg, 1 mmol), and N-Boc-L-serine (205 mg,
1 mmol) were reacted according to the general macrocyclization
procedure. Flash column chromatography purification (CH2Cl2–
MeOH 10 : 1) afforded macrocycle 3 (170 mg, 43%) as a white
solid. Rf = 0.25 (CH2Cl2–MeOH 3 : 1). m.p. (from EtOAc): 172–
173 ◦C. IR (KBr): 3402, 3322, 3073, 2944, 1695, 1682, 1668, 1232,
1217, 1157, 1051. 1H NMR (CDCl3): d = 7.35 (m, 4H, Ph); 5.67
(m, 1H, NH); 5.57 (m, 1H, NH); 5.16 (br. s, 2H, NH); 4.40–
4.37 (m, 4H, CH2); 4.33 (d, 4H, J= 6.7 Hz, CH2); 4.27–4.23 (m,
4H, CH2); 3.64–3.60 (m, 4H, CH2); 3.39 (m, 4H, CH2); 2.48–2.44
(m, 8H, CH2); 2.37 (m, 4H, CH2); 1.60 (m, 4H, CH2); 1.43 (s,
18H, (CH3)3C). 13C NMR (CDCl3): d = 169.7, 169.3, 168.9, 168.6,
155.8, 154.0, 137.5, 136.3, 128.5, 128.2, 128.1, 128.0, 80.8, 54.6,
55.6, 52.7, 51.6, 50.5, 46.7, 42.6, 42.1, 39.7, 29.6, 28.8, 28.6, 28.5,
24.8. HRMS (ESI-FT-ICR) m/z: 791.4677 [M + H]+; calcd. for
C38H63O10N9: 791.4662.
Macrocycle 8
Diisocyanide 6 (110 mg, 0.5 mmol), diamine 2 (100 mg, 0.5 mmol),
paraformaldehyde (30 mg, 1 mmol), and N-Cbz-L-glutamine
(280 mg, 1 mmol) were reacted according to the general macrocy-
clization procedure. Flash column chromatography purification
(CH2Cl2–MeOH 10 : 1) afforded 8 (191 mg, 38%) as a white
solid. Rf = 0.21 (CH2Cl2–MeOH 3 : 1). m.p. (from MeOH): 207–
208 ◦C. IR (KBr): 3317, 3064, 2953, 1697, 1693, 1635, 1467, 1248,
1211, 1168. 1H NMR (CDCl3): d = 9.72 (br. s, 1H, NH); 9.58 (br. s,
1H, NH); 7.66 (d, 2H, J = 8.8 Hz, m-PhNH); 7.57 (d, 2H, J =
8.9 Hz, m-PhNH); 7.35 (m, 10H, Ph-Cbz); 6.94 (d, 2H, J = 9.2 Hz,
o-PhNH); 6.87 (d, 2H, J = 9.1 Hz, o-PhNH); 5.50 (br. s, 2H, NH);
5.10 (m, 4H, CH2); 4.94–4.89 (m, 2H, CH2); 4.60–4.56 (m, 2H,
CH2); 4.37–4.31 (m, 4H, CH2); 4.21–4.18 (m, 2H, CH2); 4.05 (m,
2H, CH2); 3.71–3.64 (m, 4H, CH2); 3.20 (m, 4H, CH2); 2.40–2.21
(m, 8H, CH2); 1.60 (m, 4H, CH2). 13C NMR (CDCl3): d = 173.8,
172.6, 168.1, 166.9, 156.6, 156.2, 136.4, 130.1, 128.4, 128.0, 122.3,
121.7, 120.5, 120.1, 66.6, 55.0, 53.6, 52.3, 52.2, 51.4, 40.0, 31.8,
29.6, 22.6, 22.4, 14.0. HRMS (ESI-FT-ICR) m/z: 1105.4767 [M +
H]+; calcd. for C52H65O11N10: 1105.4761.
Macrocycle 5
Diisocyanide 1 (78 mg, 0.5 mmol), diamine 4 (74 mg, 0.5 mmol),
paraformaldehyde (30 mg, 1 mmol), and N-Boc-L-histidine
(158 mg, 1 mmol) were reacted according to the general macro-
cyclization procedure. Flash column chromatography purification
(CH2Cl2–MeOH 10 : 1) afforded the macrocycle 5 (163 mg, 39%) as
a white solid. Rf = 0.41 (CH2Cl2–MeOH 3 : 1). m.p. (from EtOAc):
137–139 ◦C. IR (KBr): 3336, 2976, 2930, 1698, 1692, 1679, 1653,
N-Protected d-guanidinium butyric ester 12 and acid 13
A solution of methyl 4-aminobutanoate hydrochloride 9 (306 mg,
2.0 mmol), Et3N (0.28 mL, 2.0 mmol) and 2,4-dimethoxy-
benzaldehyde (276 mg, 1.7 mmol) in MeOH (20 mL) was stirred
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for 2 h at room temperature. NaBH4 (114 mg, 3.0 mmol) was
added to the reaction mixture in small portions and the reaction
mixture was stirred for additional 2 h. The solution was diluted
with diethyl ether (20 mL) and treated carefully with 10% aqueous
NaOH (10 mL). Then the organic layer was separated, washed
with water (2 × 10 mL) and brine (10 mL) and dried over
anhyd. Na2SO4 to afford the amine 10. A solution of this crude
product in DMF (2.5 mL) was treated with N-pmc-1-H-pyrazole-
1-carboxamidine 11 (800 mg, 2.1 mmol) and the reaction mixture
was stirred at 130 ◦C for 24 h in a sealed tube. After cooling to room
temperature, the solution was diluted with EtOAc (30 mL), washed
with saturated aqueous NH4Cl (10 mL) and brine (10 mL), dried
over anhyd. Na2SO4 and concentrated under pressure to furnish
a crude product. Flash column chromatography purification (n-
hexane–EtOAc 1 : 1) afforded the pure compound 12 (874 mg,
76%) as a white solid. m.p. (from CH2Cl2–n-hexane): 145–146 ◦C.
1H NMR (CDCl3): d = 7.01 (d, 1H, J = 8.4 Hz, CH); 6.61 (br. s,
1H, NH); 6.41 (s, 1H, CH); 6.34 (d, 1H, J = 7.2 Hz, CH), 4.41 (s,
2H); 3.77 (s, 3H, CH3O); 3.76 (s, 3H, CH3O); 3.64 (s, 3H, CH3O);
3.29 (m, 2H, CH2); 2.61 (t, 2H, J = 6.8 Hz, CH2); 2.57(s, 3H,
CH3); 2.56 (s, 3H, CH3); 2.26 (t, 2H, J = 6.6 Hz, CH2); 2.09 (s, 3H,
CH3); 1.80 (m, 2H, CH2); 1.30 (s, 6H, CH3). 13C NMR (CDCl3):
d = 173.2, 160.4, 157.6, 155.4, 153.0, 135.3, 134.6, 133.9, 130.0,
123.6, 117.6, 104.2, 98.4, 73.4, 60.3, 55.4, 51.8, 46.6, 45.6, 32.9,
30.4, 30.3, 26.8, 22.4, 21.4, 18.5, 17.5, 14.3, 12.0. HRMS (ESI-
FT-ICR) m/z: 598.2571 [M + Na]+; calcd. for C29H41N3NaO7S:
598.2567.
156.8 [M + H]+; calcd. for C10H9N2: 157.0. The compound should
be stored at 4 ◦C to avoid decomposition.
1,4-Bis(3-isocyanopropyl)piperazine (16)
Diamine 2 (3.6 g, 22.0 mmol) was treated in a similar way as
described for the synthesis of 15 to afford the diisocyanide 16
(4.01 g, 84%) as a pale yellow solid. Rf = 0.37 (CH2Cl2–MeOH
10 : 1). m.p. (from EtOH): 79–81 ◦C. IR (KBr, cm−1): 2814, 2153,
1462, 1283, 1159, 1143. 1H NMR (CDCl3): d = 3.47 (tt, 4H, J =
6.6/1.9 Hz, CH2); 2.47 (t, 4H, J = 6.8 Hz, CH2); 2.46 (m, 8H,
CH2); 3.47 (qt, 4H, J = 6.7/2.0 Hz, CH2). 13C NMR (CDCl3): d =
155.7, 155.6, 54.4, 53.1, 39.6, 39.5, 39.4, 26.5. HRMS (ESI-FT-
ICR) m/z: 243.1578 [M + Na]+; calcd. for C12H20NaN4: 243.1580.
1,8-Diisocyano-3,6-dioxaoctane (17)
Diamine 4 (5 g, 24 mmol) was treated in a similar way as described
for the synthesis of 15 to afford the diisocyanide 17 (3.91 g,
69%) as a pale brown oil. Rf = 0.47 (CH2Cl2–MeOH 10 : 1). IR
(ATR, cm−1): 2927, 2151, 1254, 1206, 1178, 1159, 1103. 1H NMR
(CDCl3): d = 3.74–3.71 (m, 8H, CH2); 3.60 (t, 4H, J = 5.8 Hz,
CH2). 13C NMR (CDCl3): d = 157.0, 156.9, 70.7, 68.6, 41.9, 41.8,
41.7. HRMS (ESI-FT-ICR) m/z: 191.0788 [M + Na]+; calcd. for
C8H12NaN2O2: 191.0790. The compound should be stored at 4 ◦C
to avoid decomposition.
LiOH (233 mg, 3.7 mmol) was added to a solution of ester 12
(850 mg, 1.48 mmol) in THF–H2O (2 : 1, 50 mL) at 0 ◦C. The
reaction mixture was stirred at 0 ◦C for 2 h and then acidified with
10% aq. NaHSO4 to pH 3. The resulting phases were separated
and the aqueous phase was further extracted with EtOAc (2 ×
60 mL). The combined organic phases were dried over anhyd.
Na2SO4 and concentrated under reduced pressure to afford the
acid 13 (814 mg, 98%) as a white solid. The product (identified
by ESI-MS) was used in the macrocyclization without further
purification and characterization.
Macrocycle 19
Diisocyanide 17 (84 mg, 0.5 mmol), diamine 18 (68 mg,
0.5 mmol), paraformaldehyde (30 mg, 1 mmol), and N-protected
d-guanidinium butyric acid 13 (561 mg, 1 mmol) were reacted ac-
cording to the general macrocyclization procedure. Flash column
chromatography purification (CH2Cl2–MeOH 15 : 1) afforded the
macrocycle 19 (276 mg, 38%) as a pale yellow solid. Rf = 0.43
(CH2Cl2–MeOH 10 : 1). m.p. (from EtOAc): 187–190 ◦C. IR
(KBr): 3021, 2918, 2850, 1728, 1626, 1541, 1506, 1463, 1258, 1209,
1107, 759. 1H NMR (CDCl3): d = 7.26 (m, 4H, CH-Ph); 7.01 (d,
1H, J = 8.4 Hz, CH-Ph); 6.43 (s, 2H, CH); 6.37 (m, 2H, J= 7.2 Hz,
CH-Ph), 5.37–5.32 (m, 2H, NH); 4.47–4.42 (s, 4H); 4.32–4.25 (m,
4H); 3.78 (s, 6H, CH3O); 3.76 (s, 6H, CH3O); 3.62–3.57 (m, 4H);
3.39–3.28 (m, 6H); 3.31–3.27 (m, 4H, CH2); 3.25–3.20 (m, 4H,
CH2); 3.06–2.07 (m, 4H, CH2); 2.62–2.60 (m, 4H); 2.56 (s, 6H,
CH3); 2.54 (s, 6H, CH3); 2.31–2.28 (m, 4H); 2.11 (s, 6H, CH3);
1.31 (s, 12H, CH3). 13C NMR (CDCl3): d = 171.7, 170.9, 169.7,
169.6, 169.3, 160.4, 160.2, 157.8, 155.3, 153.4, 153.2, 138.7, 135.9,
135.4, 134.1, 133.7, 131.2, 128.4, 128.2, 123.4, 123.3, 117.7, 177.5,
104.2, 98.2, 73.6, 60.1, 55.8, 51.6, 50.5, 48.7, 46.8, 45.3, 42.9, 33.1,
30.7, 30.5, 26.9, 22.5, 21.2, 18.7, 18.6, 17.5, 17.3, 14.3, 14.2, 12.2,
12.1. HRMS (ESI-FT-ICR) m/z: 1473.6825 [M + Na]+; calcd. for
C74H102N10NaO16S2: 1473.6812.
m,mꢀ-Diisocyanoxylene (15)
A solution of m-xylylenediamine 14 (3.0 g, 22.0 mmol) in ethyl
formate (200 mL) was stirred at reflux for 20 h. The resulting
precipitate was filtered under reduced pressure, washed with cold
EtOAc (2 × 30 mL) and dried at 60 ◦C to furnish the corresponding
diformamide. This product was dissolved in 150 mL of dry
CH2Cl2, then Et3N (40 mL) was added and the solution was
cooled to −60 ◦C. A solution of POCl3 (6.6 mL, 72 mmol) in
30 mL of CH2Cl2 was added dropwise under argon atmosphere
and the resulting reaction mixture was stirred overnight at room
temperature. Themixture was poured into cold water (200mL) and
extracted with CH2Cl2 (2 × 100 mL). The organic layer was washed
with sat. aq. NaHCO3 (100 mL), brine (100 mL), then dried over
anhyd. Na2SO4 and concentrated under reduced pressure. The
crude product was purified by column chromatography (CH2Cl2)
to afford the diisocyanide 15 (2.84 g, 83%) a pale yellow oil. Rf =
0.58 (CH2Cl2). IR (ATR, cm−1): 2123. 1H NMR (CDCl3): d = 7.45
(t, 1H, J = 6.6 Hz, CH-Ph); 7.35 (d, 2H, J = 6.8 Hz, CH-Ph);
7.32 (s, 1H, CH-Ph); 4.68 (s, 4H, CH2). 13C NMR (CDCl3): d =
157.8, 157.8, 133.0, 129.5, 126.5, 124.6, 45.3, 45.1. ESI-MS m/z:
Macrocycle 20
Diisocyanide 16 (110 mg, 0.5 mmol), diamine 18 (68 mg,
0.5 mmol), paraformaldehyde (30 mg, 1 mmol), and N-Boc-L-
tryptophan (304 mg, 1 mmol) were reacted according to the
general macrocyclization procedure. Flash column chromatog-
raphy purification (CH2Cl2–MeOH–Et3N 10 : 1 : 0.1) afforded
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the macrocycle 20 (213 mg, 43%) as a light yellow solid. Rf =
0.33 (CH2Cl2–MeOH–Et3N 5 : 1 : 0.1). m.p. (from EtOAc): 174–
175 ◦C. IR (KBr): 3313, 3011, 2941, 1652, 1540, 1457, 1254, 1215,
1166, 1011, 750. H NMR (CDCl3): d = 9.54 (br. s, 1H, NH);
9.4 Hz, CH); 4.75 (d, J = 8.5 Hz, 2H, CH); 4.54–4.49 (m, 4H,
CH2); 4.30 (dd, 2H, J = 12.3/4.5 Hz, CH); 4.13 (dd, 2H, J =
12.4/2.3 Hz, CH); 4.04 (td, 2H, J = 10.1/5.9 Hz, CH); 3.84–3.79
(m, 4H, CH2); 2.57–2.54 (m, 4H, CH2); 2.06 (s, 6H, CH3CO); 2.00
(s, 6H, CH3CO); 1.96 (s, 6H, CH3CO). 13C NMR (CDCl3): d =
173.1, 172.6, 171.8, 171.1, 170.8, 169.1, 168.4, 157.7 (q, J = 38
Hz), 157.4 (q, J = 38 Hz), 143.8, 136.3, 130.2, 128.3, 128.2, 128.0,
127.9, 115.5 (q, J = 288 Hz), 114.8 (q, J = 288 Hz), 101.3, 101.2,
73.5, 73.1, 69.9, 66.8, 63.2, 55.9, 45.9, 44.2, 40.9, 35.7, 20.9, 20.6,
20.4. HRMS (ESI-FT-ICR) m/z: 1349.3819 [M + Na]+; calcd. for
C58H64NaF6O23N6: 1349.3818.
1
8.94 (br. s, 1H, NH); 7.77–7.74 (m, 2H, CH-indole); 7.59–7.56 (m,
2H, CH-indole); 7.43 (d, 2H, J = 7.3 Hz, CH-Ph); 7.32 (d, 2H,
J = 7.4 Hz, CH-Ph); 7.15–7.00 (m, 6H, CH-indole); 6.56 (m, 1H,
NH); 6.29 (m, 1H, NH); 5.64 (br. s, 1H, NH); 5.48 (br. s, 1H,
NH); 5.38–5.33 (m, 2H, CH2); 5.24–5.18 (m, 2H, CH2); 4.83–4.80
(m, 4H, CH2); 4.59–4.54 (m, 2H, CH2); 4.48–4.45 (m, 2H, CH2);
4.39–4.34 (m, 2H, CH); 4.22–4.08 (m, 4H, CH2); 3.36–3.28 (m,
4H, CH2); 1.47, 1.44, 1.43 (s, 18H, (CH3)3C). 13C NMR (CDCl3):
d = 172.9, 172.3, 171.5, 170.7, 155.3, 155.0, 136.1, 134.9, 130.8,
129.8, 129.6, 129.1, 128.7, 128.4, 128.1, 127.2, 127.0, 126.5, 123.8,
123.5, 121.6, 121.4, 119.6, 119.2, 118.7, 117.6, 111.5, 111.2, 109.8,
109.6, 105.5, 80.6, 80.4, 77.2, 61.3, 58.4, 56.5, 56.1, 55.4, 54.9,
52.6, 52.0, 50.8, 47.5, 46.2, 37.4, 29.7, 29.4, 28.6, 28.5, 28.4, 23.3,
18.5. HRMS (ESI-FT-ICR) m/z: 989.5599 [M + H]+; calcd. for
C55H73O8N10: 989.5607.
Acknowledgements
We are grateful to the Deutsche Forschungsgemeinschaft
(GRK/894 and CERC-3), HWP-LSA and to the DAAD and
CNPq (grant to O. E. V.) for financial support.
References
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and D. G. Rivera, Targets Heterocycl. Syst., 2006, 10, 24–53; (b) F. von
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Int. Ed., 1999, 38, 2096–2152.
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A. Do¨mling, R. V. A. Orru and L. A. Wessjohann, Synthesis, 2006,
3997–4005; (b) Y. Jia, N. Ma, Z. Liu, M. Bois-Choussy, E. Gonzalez-
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5334–5351; (c) J. Chatterjee, D. Mierke and H. Kessler, J. Am. Chem.
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Sasmal, G. Rassias, M. V. Reddy, K.-H. Altmann, M. Wartmann, A.
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Macrocycle 22
Diisocyanide 15 (78 mg, 0.5 mmol), L-lysine ethyl ester dihy-
drochloride (124 mg, 0.5 mmol), Et3N (0.128 mL, 1 mmol),
paraformaldehyde (30 mg, 1 mmol), and N-Boc-L-glutamic acid
5-benzyl ester (337 mg, 1 mmol) were reacted according to the
general macrocyclization procedure. Flash column chromatogra-
phy purification (CH2Cl2–MeOH 15 : 1) afforded the macrocycle
22 (206 mg, 40%) as a white solid. Rf = 0.33 (CH2Cl2–MeOH
10 : 1). m.p. (from n-hexane–CH2Cl2): 82–84 ◦C. IR (KBr): 2979,
1
2944, 1732, 1697, 1654, 1522, 1454, 1248, 1167, 1029, 751. H
NMR (CDCl3): d = 7.88 (m, 1H, NH); 7.79 (m, 1H, NH); 7.35
(m, 5H, Bn); 7.34–7.33 (m, 6H, Bn + CH-Ph); 7.23 (s, 1H, CH-Ph);
7.19 (d, 2H, J = 6.9 Hz, CH-Ph); 5.32 (d, 1H, J = 8.0 Hz, NH);
5.25 (d, 1H, J = 7.9 Hz, NH); 5.15 (m, 2H, CH2-Bn); 5.11 (m, 2H,
CH2-Bn); 4.89–4.86 (m, 1H, CH); 4.72–4.67 (m, 1H, CH); 4.50–
4.40 (m, 3H, CH2 + CH); 4.18–4.07 (m, 4H, CH2); 2.55–2.44 (m,
4H, CH2); 1.44 (s, 9H, (CH3)3C); 1.40 (s, 9H, (CH3)3C); 1.21 (t,
3H, J = 7.1 Hz, CH3). 13C NMR (CDCl3): d = 173.2, 172.7, 170.7,
168.4, 168.3, 167.9, 167.6, 156.4, 156.1, 138.9, 138.4, 135.5, 128.4,
128.2, 128.1, 128.0, 80.4, 80.1, 66.6, 61.9, 61.5, 58.0, 50.8, 50.0,
49.3, 43.7, 43.4, 43.0, 29.6, 29.2, 28.6, 28.4, 28.3, 27.2, 26.9, 23.4,
14.2. HRMS (ESI-FT-ICR) m/z: 1051.5008 [M + Na]+; calcd. for
C54H72O14NaN6: 1051.4999.
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Macrocycle 24
Diisocyanide 6 (110 mg, 0.5 mmol), diamine 14 (68 mg, 0.5 mmol),
paraformaldehyde (30 mg, 1 mmol), and the aminosugar-derived
acid 23 (489 mg, 1 mmol) were reacted according to the gen-
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(232 mg, 35%) as a pale brown solid. Rf = 0.37 (CH2Cl2–MeOH
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◦
1
5 : 1). m.p. (from EtOAc): 231–233 C. H NMR (CDCl3): d =
9.65 (br. s, 1H, NH); 9.54 (br. s, 1H, NH); 7.63 (d, 2H, J = 8.9 Hz,
m-PhNH); 7.54 (d, 2H, J = 8.9 Hz, m-PhNH); 6.92 (d, 2H, J =
9.1 Hz, o-PhNH); 6.84 (d, 2H, J = 9.0 Hz, o-PhNH); 7.31 (t,
1H, J = 7.6 Hz, CH-Ph); 7.29 (s, 1H, CH-Ph); 7.19 (d, 2H, J =
7.2 Hz, CH-Ph); 5.27 (t, 2H, J = 9.9 Hz, CH); 5.00 (t, 2H, J =
6 (a) S. Ueda, S. Oishi, Z. Wang, T. Araki, H. Tamamura, J. Cluzeau, H.
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