Expedient synthesis of a novel asymmetric selectively deprotectable derivative of the ATAC scaffold

An efficient multigram scale synthesis of a new asymmetric triazacyclophane scaffold, the ATAC (Asymmetric-TAC) scaffold, bearing three selectively removable groups is described. This scaffold is slightly more rigid than our frequently used TAC (TriAzaCyclophane) scaffold. The synthesis of the required triamine is very high yielding without difficult steps or purifications and was also applied to a much improved synthesis of our original TAC scaffold. Especially the tedious first reaction step, that is, mono-oNBS-protection of a triamine could be omitted. The rigidity of the triazacyclophane ring in both TAC- and ATAC scaffolds has also been investigated using variable temperature ¹H NMR experiments.     

Synthesis of a polypseudorotaxane, polyrotaxane, and polycatenane using ‘click’ chemistry

The synthesis of a polypseudorotaxane, polyrotaxane, and polycatenane containing the electron-deficient cyclophane cyclobis(paraquat-p-phenylene) (CBPQT⁴⁺) subunit in the side chain is described. These interlocked supramolecular polymers have been prepared from an azide-functionalized polystyrene derivative and an acetylene-functionalized [2]rotaxane, [2]catenane and their parent tetracationic cyclophane via Cu(I)-catalyzed 1,3 dipolar cycloadditions (‘click chemistry’). The synthesis and characterization of the polymers and intermediates has been described using IR, ¹H NMR, UV spectroscopies, and voltammetry. We have shown that the CBPQT⁴⁺ unit of the side chain polystyrene derivative has the ability to reversibly undergo complexation with a complementary dialkoxynaphthalene derivative.     

The Synthesis of D‐Trihydroxyllysine‐Based Oligopeptides as a Hydrophilic Scaffold and its Application to the Synthesis of Bifunctional Chelating Agents for Use as Bone Tracers

An effective hydrophilic scaffold composed of D ‐trihydroxyllysine‐based oligopeptides and its application in the synthesis of the various ¹¹¹In–DTPA conjugates with mono‐ to penta‐bisphosphonate units for use as bone tracers are described. The D ‐trihydroxyllysine derivative with three orthogonal protecting groups was conjugated with functional devices at the γ position and allowed oligomerization based on peptide chemistry. The radiopharmaceutical complexes of ¹¹¹In^III with selected chelators, 4 and 8 , were suitable for bone imaging. These results show that D ‐trihydroxyllysine 2 was an effective building block for the synthesis of multivalent ligands applicable to medical use.     

A direct route for the preparation of Fmoc/OtBu protected iodotyrosine

Herein the synthesis of an Fmoc/O^tBu orthogonally protected iodotyrosine derivative is reported. This has been achieved via a simple two-step process in an overall 58% yield from commercially available Fmoc-Tyr(^tBu)-OH. The Fmoc/O^tBu orthogonally protected iodotyrosine was also shown to be amenable to Suzuki-Miyaura cross-coupling to deliver a novel bi-aryl tyrosine derivative.     

A convenient synthesis of new chromophoric tetracyanobutadiene-scaffolded peptides via a dipolar [2+2] cycloaddition-cycloreversion reaction

Herein, we report a novel approach for the synthesis of π-conjugated peptide-based donor-acceptor (D-π-A) chromophores, by reacting electron-rich alkynes with tetracyanoethylene. The desired tetracyanobutadiene-scaffolded peptides were obtained in good yields with various optical properties, λ_max: 321-492 nm, ε: 21,000-65,000 mol⁻¹ dm³ cm⁻¹ depending on the substitution pattern of the cyanobutadiene scaffold.     

Solid-Phase Synthesis of Selectively Mono-Fluorobenz(o)ylated Polyamines as a Basis for the Development of 18F-Labeled Radiotracers

Polyamines are highly attractive vectors for tumor targeting, particularly with regards to the development of radiolabeled probes for imaging by positron emission (PET) and single-photon emission computed tomography (SPECT). However, the synthesis of selectively functionalized derivatives remains challenging due to the presence of multiple amino groups of similar reactivity. In this work, we established a synthetic methodology for the selective mono-fluorobenz(o)ylation of various biogenic diamines and polyamines as lead compounds for the perspective development of substrate-based radiotracers for targeting polyamine-specific membrane transporters and enzymes such as transglutaminases. For this purpose, the polyamine scaffold was constructed by solid-phase synthesis of the corresponding oxopolyamines and subsequent reduction with BH₃/THF. Primary and secondary amino groups were selectively protected using Dde and Boc as protecting groups, respectively, in orientation to previously reported procedures, which enabled the selective introduction of the reporter groups. For example, N¹-FBz-spermidine, N⁴-FBz-spermidine, N⁸-FBz-spermidine, and N¹-FBz-spermine and N⁴-FBz-spermine (FBz = 4-fluorobenzoyl) were obtained in good yields by this approach. The advantages and disadvantages of this synthetic approach are discussed in detail and its suitability for radiolabeling was demonstrated for the solid-phase synthesis of N¹-[¹⁸F]FBz-cadaverine.     

Enantiospecific synthesis of 3-aza-6,8-dioxa-bicyclo[3.2.1]octane carboxylic acids from erythrose

New methodology for the synthesis of enantiopure 3-aza-6,8-dioxa-bicyclo[3.2.1]octane-carboxylic acids belonging to 7-endo-BTAa sub-class of γ/δ amino acids is described. The novelty is the use of 2,3-O-isopropylidene-erythrose instead of meso-tartaric acid derivative, thus allowing us to perform an enantiospecific synthesis. Reductive amination of erythrolactol with aminoacetaldehyde diethylacetal or benzylamine, and subsequent acid cyclisation gave directly the amino alcohol scaffold. Protection of nitrogen as urethane and final alcohol oxidation afforded the Fmoc-, Boc-, and Cbz-amino acids. The new synthetic route was applied to multigram scale, thus resulting in a marked improvement of the synthesis of enantiopure 7-endo-BTG and 7-endo-BTK amino acids.     

Tricine as a convenient scaffold for the synthesis of C-terminally branched collagen-model peptides

A novel and convenient method for the synthesis of C-terminally branched collagen-model peptides has been achieved using tricine (N-[tris(hydroxymethyl)methyl]glycine) as a branching scaffold and 1,2-diaminoethane or 1,4-diaminobutane as a linker. The peptide sequence was incorporated directly onto the linker and scaffold during solid-phase synthesis without additional manipulations. The resulting branched triple-helical peptides exhibited comparable thermal stabilities to the parent, unbranched sequence, and served as substrates for matrix metalloproteinase-1 (MMP-1). The tricine-based branch reported herein represents the simplest synthetic scaffold for the convenient synthesis of covalently linked homomeric collagen-model triple-helical peptides.     

exo-N-[2-(4-Azido-2,3,5,6-tetrafluorobenzamido)ethyl]-dC: a novel intermediate in the synthesis of dCTP derivatives for photoaffinity labelling

An alternative route for the synthesis of a photoaffinity labelling (PAL) dCTP derivative is reported. This method involves the intermediacy of exo-N-[2-(4-azido-2,3,5,6-tetrafluorobenzamido)ethyl]-dC. The latter is prepared from the coupling of known N-(2-aminoethyl)-4-azido-2,3,5,6-tetrafluorobenzamide, prepared in an improved three-step sequence, with an activated 4-triazolyl derivative of dU, followed by deprotection. ¹⁹F NMR spectroscopy proved extremely useful in following the synthetic transformations, and enabled control of any adventitious reduction of the azides.     

Chemical and enzymatic synthesis of glycocluster having seven sialyl lewis X arrays using β-cyclodextrin as a key scaffold material

An efficient and practical method for the large-scale synthesis of an anti-inflammatory glycocluster having seven sialyl Lewis X (SLeX) residues was established on the basis of chemical and enzymatic strategy from β-cyclodextrin (β-CD) as a key starting scaffold material. A key intermediate, β-CD derivative having seven N-acetyl-d-glucosamine (GlcNAc) residues [(GlcNAc)₇CD], was prepared by a coupling reaction with heptakis 6-deoxy-6-iodo-β-cyclodextrin and sodium thiolate containing a GlcNAc residue. Subsequent sugar elongation reactions of (GlcNAc)₇CD proceeded smoothly by means of β-1,4-galactosyltransferase, α-2,3-sialyltransferase, and α-1,3-fucosyltransferase V in the presence of the corresponding sugar nucleotides (UDP-Gal, CMP-Neu5Ac, and GDP-Fuc) and allowed to give a mono-dispersed glycodendrimer (M_w=7924.5, calcd for C₃₀₁H₄₉₀N₂₁O₁₉₆S₇Na₇; MALDI-TOF MS, m/z 7946 [M+Na]⁺) that completely substituted with seven SLeX branches at C-6 positions in excellent overall yield (74%, 3 steps). Hyper-branched glycodendrimer, (SLeX)₇CD, exhibited highly amplified inhibitory effect on the interaction of E-selectin with SLeXn-BSA immobilized on the sensor chip by means of surface plasmon resonance method.     

Synthesis of a tetra-deuterium-labeled derivative of potent and selective anticancer agent AA005

Annonaceous acetogenins are a series of potent naturally occurring anticancer agents, which act as inhibitors of complex I in mitochondria. AA005, a mimicry of acetogenins, has been found as active as those natural products and to present high selectivities between cancer and normal cells. In order to investigate the further cell-based mechanism induced by AA005, a d⁴-labeled derivative of AA005 (AA005-d⁴) was designed to detect the drug permeation ability into the membranes. In this letter, the synthesis is reported of this deuterium-labeled compound, wherein a ethylene-d⁴ glycol unit is incorporated efficiently into the molecule skeleton by simple etherifications.     

Design and synthesis of a novel protected mixed ligand siderophore

A novel siderophore analog (4) has been designed to facilitate iron transport-mediated drug delivery and drug release. This mixed ligand siderophore analog includes three bidentate ligands intended to octahedrally coordinate iron (III). The ligands include a 2,3-dihydroxy benzoic acid moiety, N⁵-acetyl-N⁵-hydroxy-l-ornithine, and a β-N-hydroxy-α,β-diaminopropionic acid derivative. The total synthesis of 15, a form of 4 that is suitably protected, yet contains a free carboxylic acid for subsequent drug conjugation, is described.     

Synthesis of a fluorescent 14-crown-4 derivative bearing a proton-dissociable moiety and its use for selective lithium-ion extraction

The fluorescent 14-crown-4 derivative possesses a p-(1,8-naphthalenedicarboxi-mido) phenol moiety as the proton -dissociable fluorophore; its synthesis is described. Highly selective extraction of lithium is achieved with the crown ether, based on a proton/metal ion-exchange mechanism. Extraction is accompanied by significant changes in the absorption and fluorescence spectra of the organic phase. Extraction equilibrium constants for the lithium and sodium ions are evaluated, the Li⁺/Na⁺ selectivity ratio being 200; other alkali metal ions were not extracted. The Li⁺ extraction quenched the fluorescence intensity of the crown ether, in correlation with the initial cation concentration in the aqueous phase.     

Synthesis of a novel polycyclic ring scaffold with antimitotic properties via a selective domino Heck–Suzuki reaction

The synthesis of a previously undescribed sp³-rich 6-5-5-6 tetracyclic ring scaffold using a palladium catalysed domino Heck–Suzuki reaction is reported. This reaction is high-yielding, selective for the domino process over the direct Suzuki reaction and tolerant towards a variety of boronic acids. The novel scaffold can also be accessed via domino Heck–Stille and radical cyclisations. Compounds based around this scaffold were found to be effective antimitotic agents in a human cancer cell line. Detailed phenotypic profiling showed that the compounds affected the congression of chromosomes to give mitotic arrest and apoptotic cell death. Thus, a novel structural class of antimitotic agents that does not disrupt the tubulin network has been identified.     

Convenient synthesis of novel N-(5-allyl-7,7-difluoro)-4,5,6,7-tetrahydro-2H-indazol-3-yl)-carboxymides

5-Allyl-7,7-difluoro-2-(2,4-difluorophenyl)-6-(4-methoxyphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-3-amine represents a fluorinated heterocyclic scaffold, potentially attractive. It was synthesized via Michael addition, Mannich reaction of the difluorinated ethyl bromoacetate with a benzotriazole derivative, followed by a Dieckmann condensation. Starting from simple materials, this efficient route which gives access to novel functionalized N-(5-allyl-7,7-dihalo)-4,5,6,7-tetrahydro-2H-indazol-3-yl)-carboxymides, was explored and adapted for parallel synthesis, resulting in a compound library.     

Synthesis and NMR characterization of a novel crown-ether ring-fused uridine analogue

The chemical synthesis and ¹H NMR analysis of a novel bicyclic uridine derivative, with a 18-crown-6 ether moiety fused at the ribose 2- and 3-positions, as first example of a hitherto unknown class of ribose-modified nucleosides, are here described. NMR-based conformational analysis studies showed for the modified nucleoside a marked preference for an N-type sugar puckering and the nucleobase in the anti conformation, with the uracil favouring the coordination of a sodium ion hosted in the crown ether.     

Foldamers of bifunctional diketopiperazines displaying a β-bend ribbon structure

The synthesis of two oligomers, of a bifunctional diketopiperazine scaffold DKP-1, formally derived from the cyclization of l-aspartic acid and (S)-2,3-diaminopropionic acid, is reported. A trimeric and a tetrameric structure were prepared by solution-phase peptide synthesis (Boc strategy). Conformational analysis of these derivatives was carried out by a combination of ¹H NMR spectroscopy, CD spectroscopy, and molecular modeling, and revealed the formation of β-bend ribbon involving 10-membered H-bonded rings and a reverse turn of the growing peptide chain.     

7,8,9-trimethyl-1-phenyl-3<Emphasis Type="Italic">H</Emphasis>-pyrrolo[2,1-<Emphasis Type="Italic">d</Emphasis>][1,2,5]triazepin-4(5<Emphasis Type="Italic">H</Emphasis>)-one. Synthesis and reactions

A strategy was developed for the synthesis of 7,8,9-trimethyl-1-phenyl-3H-pyrrolo[2,1-d][1,2,5]-triazepin-4(5H)-one, reactions of its functionalization at the С⁴ atom and aza rings fusion at the С⁴?N³ bond were explored. The formation mechanism of the pyrrolo-1,2,5-triazepinone scaffold was suggested.     

The unambiguous synthesis and NMR assignment of 4-alkoxy and 3-alkylquinazolines

Contrary to a number of reports, alkylations of the privileged 3,4-dihydroquinazoline scaffold provide N3-alkylated products, and not 4-alkoxyquinazolines. To correctly assign the structure, ¹³C NMR shifts of the –Z–CH_n– (Z=O, N) fragment are necessary; resonances in the 45–55 ppm range are indicative of N3-alkylation. Treatment of 3,4-dihydroquinazoline-4-one with p-TsCl afforded the N3-tosylated compound, whose reaction with an amine yielded the corresponding N3-alkyl derivative. A mechanism corroborated by ¹⁵N-labeling involving pyrimidine ring opening and recyclisation is proposed. Finally, the unambiguous preparation of 4-alkoxyquinazolines is described via treatment of 3,4-dihydroquinazoline-4-ones with PCl₅ followed by an alkoxide.     

Assymetric synthesis of (2S,3R)- and (2S,3S)-[2-C;3-H] glutamic acid

We have developed a synthetic route for (2S,3R)- and (2S,3S)-[2-¹³C;3-²H] glutamic acids with high enantioselectivity. The key reactions in this synthesis are the asymmetric reduction of the 2,3-didehydroornithine derivative using the (S,S)-Et-DuPHOS-Rh catalyst and the oxidation of the δ-position by ruthenium catalysis.