Cyclative Cleavage Research Articles

I2-Promoted site-selective C–C bond cleavage of aryl methyl ketones as C1 synthons for constructing 5-acyl-1H-pyrazolo[3,4-b]pyridines

A novel iodine promoted [1 + 3 + 2] cleavage cyclization reaction for the synthesis of 1H-pyrazolo[3,4-b]pyridines from aryl methyl ketones, 5-aminopyrazoles and enaminones has been established.

Synthesis of new pyrazolo[1,2,3]triazines by cyclative cleavage of pyrazolyltriazenes

We describe the synthesis of so far synthetically not accessible 3,6-substituted-4,6-dihydro-3H-pyrazolo[3,4-d][1,2,3]triazines as nitrogen-rich heterocycles. The target compounds were obtained in five steps, including an amidation and a cyclative cleavage reaction as key reaction steps. The introduction of two side chains allowed a variation of the pyrazolo[3,4-d][1,2,3]triazine core with commercially available building blocks, enabling the extension of the protocol to gain other derivatives straightforwardly. Attempts to synthesize 3,7-substituted-4,7-dihydro-3H-pyrazolo[3,4-d][1,2,3]triazines, the regioisomers of the successfully gained 3,6-substituted 4,6-dihydro-3H-pyrazolo[3,4-d][1,2,3]triazines, were not successful under similar conditions due to the higher stability of the triazene functionality in the regioisomeric precursors and thus, the failure of the removal of the protective group.

A trifunctional self-immolative spacer enables drug release with two non-sequential enzymatic cleavages.

Cyclative cleavage of an amine-carbamate self-immolative spacer to deliver a hydroxyl cargo was inhibited by spacer derivatisation with a phosphate monoester handle. This trifunctional spacer was installed in a model anticancer prodrug that showed fast drug release only when incubated with both a protease and a phosphatase enzyme.

Solid-Phase Synthesis of Head to Side-Chain Tyr-Cyclodepsipeptides Through a Cyclative Cleavage From Fmoc-MeDbz/MeNbz-resins.

Cyclic depsipeptides constitute a fascinating class of natural products. Most of them are characterized by an ester formed between the β-hydroxy function of Ser/Thr -and related amino acids- and the carboxylic group of the C-terminal amino acid. Less frequent are those where the thiol of Cys is involved rendering a thioester (cyclo thiodepsipeptides) and even less common are the cyclo depsipeptides with a phenyl ester coming from the side-chain of Tyr. Herein, the preparation of the later through a cyclative cleavage using the Fmoc-MeDbz/MeNbz-resin is described. This resin has previously reported for the synthesis of cyclo thiodepsipeptides and homodetic peptides. The use of that resin for the preparation of all these peptides is also summarized.

An ICT-based fluorescent probe with a large Stokes shift for measuring hydrazine in biological and water samples

As a strong reductant and highly active alkali, hydrazine (N2H4) has been widely used in chemical industry, pharmaceutical manufacturing and agricultural production. However, its high acute toxicity poses a threat to ecosystem and human health. In the present study, a ratiometric fluorescent probe for the detection of N2H4 was designed, utilizing dicyanoisophorone as the fluorescent group and 4-bromobutyryl moiety as the recognition site. 4-(2-(3-(dicyanomethylene)-5,5-dimethylcyclohex-1-enyl) phenyl 4-brobutanoate (DDPB) was readily synthesized and could specially sense N2H4 via an intramolecular charge transfer (ICT) pathway. The cyclization cleavage reaction of N2H4 with a 4-bromobutyryl group released phenolic hydroxyl group and reversed the ICT process between hydroxy group and fluorophore, turning on the fluorescence in the DDPB-N2H4 complexes. DDPB exhibits a low cytotoxicity, reasonable cell permeability, a large Stokes shift (186 nm) and a low detection limit (86.3 nM). The quantitative determination of environmental water systems and the visualization fluorescence of DDPB test strips provides a strong evidence for the applications of DDPB. In addition, DDPB is suitable for the fluorescence imaging of exogenous N2H4 in HeLa cells and zebrafish.

An Improved Synthetic Protocol for Benzothiazoles via Ring Opening of Benzotriazole

AbstractAn improved procedure for the construction of benzothiazole scaffold via intramolecular cyclative cleavage of benzotriazole ring under free radical condition was successfully accomplished. The protocol utilises NaBH4 which regenerates the active reagent n‐Bu3SnH in the reaction medium and makes this method cost effective and less toxic as a substitute of expensive and toxic silanes.

Convenient Synthesis of Thiohydantoins, Imidazole-2-thiones and Imidazo[2,1-b]thiazol-4-iums from Polymer-Supported α-Acylamino Ketones.

The preparation of 5-methylene-thiohydantoins using solid-phase synthesis is reported in this paper. After sulfonylation of immobilized Ser (t-Bu)-OH with 4-nitrobenzenesulfonyl chloride followed by alkylation with various bromoketones, the 4-Nos group was removed and the resulting polymer-supported α-acylamino ketones reacted with Fmoc-isothiocyanate. Cleavage of the Fmoc protecting group was followed by the spontaneous cyclative cleavage releasing the 5-methylene-thiohydantoin derivatives from the polymer support. Reduction with triethylsilane (TES) yielded the corresponding 5-methyl-thiohydantoins. When Fmoc-isothiocyanate was replaced with alkyl isothiocyanates, the trifluoroacetic acid (TFA) mediated cleavage from the polymer support, which was followed by the cyclization reaction and the imidazo[2,1-b]thiazol-4-iums were obtained. Their conversion in deuterated dimethylsulfoxide led to imidazole-2-thiones.

Solid-phase synthesis of homodetic cyclic peptides from Fmoc-MeDbz-resin

Cyclic homodetic peptides are very appealing for medicinal chemistry programs. In addition to the high efficiency and selectivity inherently associated with peptides, a cyclic structure totally formed by amide bonds increases their stability under physiological conditions. Here Fmoc-MeDbz-resin was studied for the preparation of these peptides. Our results demonstrate the usefulness of this strategy for the preparation of cyclic “head-to-side chain” peptides through cyclative cleavage (simultaneous cyclization and release from the resin). In contrast, for the synthesis of the “head-to-tail” counterparts, the cyclization-cleavage should be carried out in the presence of thiophenol.

Synthesis of Disubstituted Pyrazino‐Oxazine Derivatives with Controlled Stereochemistry

Herein, we report a simple synthesis of disubstituted pyrazino‐oxazines with controlled stereochemistry using readily available building blocks: N‐Fmoc‐protected α‐amino acids and 2‐bromo ketones. The convenient solid‐phase synthesis afforded polymer‐supported derivatives of N‐alkylated N‐acylated tert‐butylserine, which were subjected to spontaneous cyclative cleavage to yield the corresponding pyrazine intermediates. The target 1,7,8,9a‐tetrahydropyrazino[2,1‐c][1,4]oxazine‐6,9‐diones were obtained in two steps by acid‐mediated cleavage of the tert‐butyl group followed by cyclization of the oxazine scaffold.

Facile solid-phase synthesis of head-side chain cyclothiodepsipeptides through a cyclative cleavage from MeDbz-resin

Head to side-chain cyclothiodepsipeptides were conveniently prepared through a cyclative cleavage using the MeDbz linker. Briefly, the peptide sequence was elongated on a MeDbz-Gly-ChemMatrix resin and reacted with 4-nitrophenyl chloroformate, followed by treatment with DIEA to render an activated cyclic N-acyl-N′-methylurea-resin. Removal of the Cys protecting group and further treatment with DIEA allowed the formation of the thiolactone with the concomitant release of the cyclic peptide from the resin.

Solid Phase Synthesis of (Benzannelated) Six-Membered Heterocycles via Cyclative Cleavage of Resin-Bound Pseudo-Oxazolones.

A solid supported procedure for the synthesis of benzoxazinones, dihydropyrazinones, quinoxalinones, and dihydrooxazinones using immobilized oxazolones in combination with difunctional nucleophiles as cleavage agent is presented. The scope of the novel method has been demonstrated through subsequent modification of the parent oxazolone scaffold on solid supports using conversions with electrophiles or CuAAC reactions to give functionalized pyrazin-2-ones. The described method allows the synthesis of the target heterocycles in good yields via three to five steps on solid phases with only one chromatographic purification step.

Solid‐Phase Synthesis of 3,4‐Dihydroquinoxalin‐2(1H)‐ones via the Cyclative Cleavage of N‐Arylated Carboxamides

AbstractWe describe a practical (time‐efficient, with commercially available building blocks, user friendly reaction conditions, high purity of products) synthesis of pharmacologically relevant quinoxalinones with three points of diversification that takes advantage of solid‐phase synthesis and cyclative cleavage. Resin‐bound (S)‐2‐(N‐alkyl‐2‐nitrophenyl)sulfonamide‐3‐alkyl‐N‐(2‐hydroxyethyl)propanamides, which are accessible from Fmoc‐protected α‐amino acids, 2‐nitrobenzenesulfonyl chloride and alcohols, underwent base‐mediated N‐arylation. The reduction of the nitro group produced acyclic intermediates that were subjected to acid‐mediated cyclative cleavage to yield 3,4‐dihydroquinoxalin‐2(1H)‐ones.magnified image

An electrochemical method to assay the activity of NAD(P)H: Quinone oxidoreductase 1

A simple and rapid electrochemical method is reported in this paper to assay the activity of NAD(P)H: quinone oxidoreductase 1 (NQO1), a potential target for anticancer therapy. Firstly, a quinone derivative, the substrate of NQO1, is designed to be covalently immobilized on the surface of gold electrode. In the presence of the enzyme, the quinone derivative transforms to the corresponding hydroquinone derivative, followed by the expected cyclizative cleavage reaction via the gem-dialkyl effect. So, the hydroquinone derivative species are released from the electrode surface into the bulk solution. As the electrochemical probe, quinone derivative can generate a pair of redox waves in aqueous buffer and its peak current is correlated with the activity of NQO1, so an electrochemical method to determine the enzyme activity can be proposed. Under the optimized conditions, NQO1 activity can be assayed in the range from 0 to 6U/mL with a detection limit of 0.22U/mL. Moreover, resveratrol, an antitumor compound, is evaluated with the maximum inhibition rate of 95% and IC50 value of 23.70μM. Therefore, with wide detection range, high sensitivity, acceptable reliability and rapid response, the established method can be used for not only the investigation of NQO1 activity but also the screening of the enzyme inhibitor.

ChemInform Abstract: Synthesis of 2‐N/S/C‐Substituted Benzothiazoles via Intramolecular Cyclative Cleavage of Benzotriazole Ring.

AbstractThe synthesis of numerous 2‐C/N/S‐substituted benzothiazoles is achieved from substituted thiocarbonylbenzotriazoles via free‐radical intramolecular cyclative cleavage of the benzotriazole ring in the presence of tris(trimethylsilyl)silane and AIBN.

Solid-phase synthesis of anagrelide sulfonyl analogues.

Simple solid-phase synthesis of 3,10-dihydro-2H-benzo[e]imidazo[1,2-b][1,2,4]thiadiazin-2-one 5,5-dioxides is described, with Fmoc-α-amino acids and 2-nitrobenzenesulfonyl chlorides (2-NosCls) being the key building blocks. Fmoc-α-amino acids were immobilized on Wang resin and transformed to the corresponding 2-nitrobenzenesulfonamides in two steps. After reduction of the nitro group, Fmoc-thioureas were synthesized followed by cyclization of the 1,2,4-benzothiadiazine-1,1-dioxide scaffold with diisopropylcarbodiimide (DIC). Cleavage of the Fmoc protecting group followed by spontaneous cyclative cleavage gave the target products in excellent crude purity.

Correction to Synthesis of 2-N/S/C-substituted Benzothiazoles via Intramolecular Cyclative Cleavage of Benzotriazole Ring

Correction to Synthesis of 2-<i>N</i>/<i>S</i>/<i>C</i>-substituted Benzothiazoles via Intramolecular Cyclative Cleavage of Benzotriazole Ring

Synthesis of 2-N/S/C-Substituted Benzothiazoles via Intramolecular Cyclative Cleavage of Benzotriazole Ring

The synthesis of numerous 2-N/S/C-substituted benzothiazoles was achieved from substituted thiocarbonylbenzotriazoles via free-radical intramolecular cyclative cleavage of the benzotriazole ring in the presence of (TMS)3SiH and AIBN under mild conditions. The developed methodology demonstrates significant compatibility under microwave conditions and is important as it avoids the use of toxic metals for radical cyclization.

Cyclization–Cleavage Strategy for the SPS of Cyclic Peptides

Cyclization–Cleavage Strategy for the SPS of Cyclic Peptides

Cyclative Cleavage of a Piperazine Amide Linker

Cyclative Cleavage of a Piperazine Amide Linker

Piperazine Amide Linker for Cyclative Cleavage from Solid Support: Traceless Synthesis of Dihydroquinoxalin-2-ones

A piperazine amide linker for cyclative cleavage from solid support and its use in the traceless solid-phase synthesis of dihydroquinoxalinones are described. Piperazine was attached to Wang resin via a carbamate linkage and acylated with Fmoc-amino acids. Following Fmoc group removal, resin-bound amines were reacted with 1-fluoro-2-nitrobenzenes. The nitro group of the resulting 2-nitroanilines was reduced, and acyclic precursors, in contrast to traditional ester-type linkage, remained attached to the resin. Target dihydroquinoxalinones were obtained either by acid- or microwave-mediated cyclative cleavage. The synthesis provided crude compounds of high purity and enabled the preparation of stable immobilized linear intermediates. The linker is suitable for combinatorial synthesis of compound libraries.