From Cyclic Peptoids to Peraza-macrocycles: A General Reductive Approach

Article abstract of DOI:10.1021/acs.orglett.9b02668

Peraza-macrocycles form chelates of high thermodynamic and kinetic stability useful in diagnostic imaging (MRI, SPECT, PET), in coordination chemistry, and as catalysts. In this letter, we report an advantageous method to prepare these compounds via BH

Full text of DOI:10.1021/acs.orglett.9b02668

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
From Cyclic Peptoids to Peraza-macrocycles: A General Reductive
Approach
Rosaria Schettini,† Assunta D’Amato,† Giovanni Pierri,† Consiglia Tedesco,† Giorgio Della Sala,†
Oriana Motta,‡ Irene Izzo,*,† and Francesco De Riccardis*,†
†Department of Chemistry and Biology “A. Zambelli”, University of Salerno, via Giovanni Paolo II, 132, Fisciano (SA), 84084, Italy
‡Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, via S. Allende, Baronissi,
Salerno (SA), 84081, Italy
S
* Supporting Information
ABSTRACT: Peraza-macrocycles form chelates of high thermodynamic and kinetic
stability useful in diagnostic imaging (MRI, SPECT, PET), in coordination chemistry,
and as catalysts. In this letter, we report an advantageous method to prepare these
compounds via BH3-induced reduction of cyclic peptoids. Using this procedure, 10
homo- and heterosubstituted aza-coronands, with different sizes and side chains, have
been synthesized from the corresponding cyclic oligoamides. Solid structures of free,
protonated, and Na+ coordinated polyaza-derivatives have been disclosed by single-
crystal X-ray diffraction analysis.
he past decades have witnessed an extraordinary
Eschweiler−Clarke methylation.2 These approaches severely
Tproliferation of metal-based pharmaceuticals with a limit the side chain diversity, also precluding the positional and
broad range of application in chemistry, biology, and
medicine.1 Complexes of toxic metals (such as Gd3+, 99mTc,
90Y) with peraza-macrocycles,2 as the NOTA-BBN (1),2e HP-
DO3A (2),3 PEPA (3),4 or the Me6[18]aneN6 (4,2c Figure 1),
are valuable diagnostic and therapeutic tools for the detection
and treatment of tumor lesions, metastases, and recurrences
after cytoreductive therapy.1
stereochemical control of the appendages.5f
The need for a general synthetic route to more efficient
peraza-macrocyclic chelators prompted us to plan an ingenious
approach based on the intra-annular amide reduction of cyclic
peptoids.6 With this straightforward approach, N-side chains
are installed early in the synthetic process and no time-
consuming postsynthetic modifications are needed to decorate
the designed polyaza-macrocycles (Figure 2). Two main
advantages differentiate the reported method when compared
with the classic ones:2,5 (1) the rapid construction of small,
medium, and large size aza-coronand employing the same
procedure; (2) the remarkable expansion of the accessible
chemical space (proportional to the number of commercially
available primary amines, potentially inserted in the precursor
linear oligomer).
With the present method, 10 macrocyclic scaffolds (from
trimeric to heptameric homo- and heterooligomeric sequen-
ces), decorated with benzyl and methoxyethyl N-side chains,
have been prepared. Furthermore, N-debenzylation of selected
macrocycles gave synthetically useful secondary amine
derivatives, useful as such or ready for possible alkylation
reactions, with the aim to extend the accessible chemical space
of these ligands.
Figure 1. Schematic structures N-substituted peraza-macrocyclic
ligands 1−4.
The quest for new and more efficient ligands (to enhance
diagnostic accuracy and reduce free metal exposure, especially
for multiple follow-up examinations and in young patients)
requires implementation of innovative synthetic methods.2
Unfortunately, synthesis of hetero- or unsymmetrically
substituted macrocycles relies on high cost cyclic precursors,
laborious protecting group manipulation, and low-yield
regioselective reactions.2a,5 Moreover, substituted peraza-
heterocycles are synthesized via alkylation of polyaza-cyclo-
alkanes by ring opening of epoxides, by alkyl halides, or by
The construction of polydentate macrocycles was accom-
plished through the classic “sub-monomer” solid-phase syn-
Received: July 29, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02668
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Table 1. Yields of Isolated Compounds for the Synthesis of
Linear Peptoids (5−14), Cyclic Peptoids (15−24), Peraza-
macrocycles (25−34), and Debenzylated Peraza-
a
macrocycles (35−37)
Synthesis of
linear peptoids:
% yield
Cyclization of
linear peptoids:
% yield
Reduction of
cyclic peptoids:
% yield
Debenzylation
reaction:
% yield
(compound)
(compound)
(compound)
(compound)
100 (5)10
100 (6)8d,10
100 (7)10
80 (8)15
90 (9)
35 (15)10
46 (16)8d,10
42 (17)10
46 (18)15
37 (19)
72 (25)6,9
75 (26)17
92 (27)
70 (28)18
77 (29)
78 (30)
91 (31)
70 (32)
100 (33)
80 (34)
−
−
−
−
−
−
−
91 (10)
34 (20)
64 (11)16
100 (12)
100 (13)
100 (14)
29 (21)16
18 (22)
95 (35)
98 (36)
89 (37)
Figure 2. Synthetic route to peraza-macrocycles via oligomerization,
cyclization, and reduction of peptoids.
32 (23)8a
23 (24)8a
a
Reaction scales for each step are reported in Schemes 1 and 2. The
thesis7 followed by high dilution cyclization,8 tertiary amide
reduction, and, when applicable, N-debenzylation.9
Linear oligomers 5−14 were produced in good to excellent
yields via solid-phase synthesis (from 64% to 100% yields,
Scheme 1 and Table 1). HATU-mediated cyclization8 gave
macrocyclic peptoids 15−24 in high purity by precipitation or
after chromatographic purification (see Supporting Informa-
synthetic steps involving the synthesis of 1,4,7,10-tetraazacyclo-
dodecane 36 (13 → 23 → 33 → 36) were repeated on a larger
scale (∼1.0 mmol) leading to comparable yields. See SI.
tion (SI)). Yields varied from 18% to 46%. Accurate NMR
analysis showed the classic all-cis “crown” conformation for
trimeric cyclic peptoid 1510 and 22 (Scheme 1).8b Homo-
(168d,10 and 20) and heterooligomeric 238a cyclotetramers
were characterized by the cis,trans,cis,trans (ctct) “chair”
arrangement, typical of these conformationally stable
oligomers, as evidenced by NMR.8b,d Interestingly, precip-
itation of 23 from ethyl acetate gave the conformational isomer
with the N-benzyl side chains on cisoid amide bonds, as
attested in the NMR spectrum by the large Δδ values detected
for the diastereotopic benzyl methylene protons (1.82 ppm;11
see SI). Larger cyclic peptoids gave fairly complex NMR
spectra due to the presence of multiple conformational isomers
in slow equilibrium on the NMR time scale8c or the lack of
symmetry.
Scheme 1. Synthesis of Peraza-macrocycles via
Oligomerization, Cyclization, and Reduction Steps
The key step for the synthesis of peraza-macrocyclic ligands
was the tertiary amide groups reduction. We tested the
efficiency of various reductive methods (NaBH4/I2; NaBH4 in
EtOH−TFE; NaBH4/Tf2O; see SI).12 One reagent, however,
surpassed all the others in terms of efficiency: the borane−
THF complex, giving 25−34 in 70%−100% yield (Table
1).6,13,14
N-Debenzylation9 of medium and large peraza-macrocycles
32−34 (in the presence of H2 and Pd/C) gave the expected
35−37 in excellent yields (Scheme 2, Table 1), ready for
subsequent N-alkylation reactions.9
The feasibility of the present approach, the large number
and amount of accessible derivatives, and the limited literature
examples of hexaperaza-macrocycles as free hosts prompted us
to characterize one of the 1,4,7,10,13,16-hexaazacycloocta-
decane derivatives synthesized with the reported procedure
(compound 28) by single-crystal X-ray diffraction analysis.
28 was crystallized by slow evaporation from a chloroform
solution. In its solid state, the macrocycle adopts a round shape
with the N-benzyl moieties almost perpendicular to the
macrocycle mean plane (Figure 3). Interestingly, the Cam-
bridge Structural Database19 reports only one crystal structure
for neutral hexa-N-substituted peraza-macrocycles20 bearing
four N-(2,3)-dihydroxybenzoyl groups and two N-methyl
groups. In the latter case the macrocycle adopts a completely
B
DOI: 10.1021/acs.orglett.9b02668
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a
Scheme 2. Partially Substituted Peraza-macrocycles 35−37
Figure 4. ORTEP drawing of compound [25·H]+ TFPB−: (a) side
and (b) top view. Ellipsoids are drawn at 20% probability level. Atom
type: C, gray; N, blue; H, white. For clarity, the TFPB anion is not
shown.
a
See SI for general procedure and Table 1 for yields.
Figure 5. ORTEP drawing of compound [26·Na]+ TFPB−: (a) side
and (b) top view. Ellipsoids are drawn at the 20% probability level.
Atom type: Na, magenta; C, gray; N, blue. For clarity, hydrogen
atoms and the TFPB anion are not shown.
Figure 3. ORTEP drawing of compound 28. Ellipsoids are drawn at
20% probability level. Atom type: C, gray; N, blue; H, white.
adduct reported by Denat and co-workers,9b and showing the
benzyl moieties folded toward the center of the macrocycle.
The X-ray crystal structure of compound [26·Na]+ TFPB−
(Figure 5) is dictated by the pseudo-octahedral coordination of
the Na+ cation. Four nitrogen atoms are coordinated to the
cation (Na−N distances within 2.45−2.55 Å), and two
opposite η3 benzyl moieties complete the first coordination
sphere (Na−C distances within 2.99−3.32 Å). The macrocycle
conformation in [26·Na]+ TFPB− is different from that evident
in the free ligand21 and similar to that observed by Habata and
co-workers in argentivorous complexes.17a
NMR titration by stepwise quantitative additions of sodium
tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaTFPB) to
CDCl3 solutions of cyclotetramer 26 showed the formation
of a metalated species (see Figure S1) displaying an upfield
shift of the benzyl ortho-protons (from 7.30 to 6.04 ppm)
similar to that observed by Habata in the presence of Ag+-
ion.17a
In recent decades, peraza-macrocyclic compounds, and
especially 1,4,7,10-tetraazacyclododecane and 1,4,7-triazacy-
clononane derivatives, have made a significant impact on the
field of diagnostic imaging1,2 and catalysis.22 Less studied, due
to the high price of the starting materials, the inefficient
methods of selective derivatization, and the limitations of the
current synthetic processes, are the 1,4,7,10,13-pentaazacyclo-
pentadecane, the 1,4,7,10,13,16-hexaazacyclooctadecane,
1,4,7,10,13,16,19-eptaazacyclohenicosane ligands, and higher
different ring conformation due to the presence of four amide
nitrogen atoms. A conformation similar to that observed in 28
was found in the recently reported K+ and Rb+ complexes of
hexa-N-methyl peraza-macrocycles.2c
We also attempted the crystallization of tridentate and
tetradentate aza-coronands 25 and 26 in the presence of
sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate
(NaTFPB). Slow evaporation of chloroform solutions
containing equimolar amounts of 25/NaTFPB and 26/
NaTFPB afforded crystals suitable for X-ray diffraction
analysis. In both cases no effort was adopted to avoid the
presence of water in the solvent.
Single-crystal X-ray diffraction revealed the formation of two
different species (protonated and sodiated) depending on the
nature of the aza-macrocyclic host.
In the presence of the 1,4,7-triazacyclononane ligand 25, the
formation of a monoprotonated adduct ([25·H]+ TFPB−,
Figure 4) was observed. In the case of the 1,4,7,10-
tetraazacyclododecane (cyclen) ligand 26, the expected Na+
complex was obtained ([26·Na]+ TFPB−, Figure 5). Formation
of different ion−molecule adducts is probably related to the
exalted coordination abilities of the cyclen ligand.
Protonation of the tridentate 1,4,7-triazacyclononane macro-
cycle (due to the basic hydrolysis of water), and plausible
precipitation of NaOH in chloroform solution, induced the
formation of the [25·H]+ TFPB−, resembling the diprotonated
C
DOI: 10.1021/acs.orglett.9b02668
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and harsh acidic conditions), we believe that previously
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Studies on the synthesis of chiral and N-bridged macro-/
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02668.
Experimental procedures, characterization data, and
HPLC chromatograms of the new compounds (PDF)
Accession Codes
CCDC 1941540−1941542 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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Thermodynamic and kinetic studies of lanthanide complexes of
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a c i d a n d 1 , 4 , 7 , 1 0 , 1 3 , 1 6 - h e x a a z a c y c l o o c t a d e c a n e -
N,N′,N′′,N′′′,N′′′′,N′′′′′-hexaacetic acid. Inorg. Chem. 1991, 30,
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: iizzo@unisa.it.
*E-mail: dericca@unisa.it.
ORCID
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Consiglia Tedesco: 0000-0001-6849-798X
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Irene Izzo: 0000-0002-0369-0102
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the University of Salerno (FARB), and
from POR CAMPANIA FESR 2014-2020 O.S.1.1.
CUPB83D18000150007 “Un approccio Integrato al Telecare
in Ambito Oncologico”. We thank Ms Oliwia Ida Rebacz,
University of Salerno, for experimental work; Dr. Patrizia
Iannece, University of Salerno, for HR-MS and elemental
analysis; and Dr. Patrizia Oliva, University of Salerno, for
NMR spectra.
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DOI: 10.1021/acs.orglett.9b02668
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