Regioselective Cyclic Iminium Formation of Ugi Advanced Intermediates: Rapid Access to 3,4-Dihydropyrazin-2(1)-ones and Other Diverse Nitrogen-Containing Heterocycles.

Herein, advanced intermediates were synthesized through Ugi four-component reactions of isocyanides, aldehydes, masked amino aldehyde, and carboxylic acids, including -protected amino acids. The presence of a masked aldehyde enabled acid-mediated deprotection and subsequent cyclization via the carbonyl carbon and the amide nitrogen. Utilizing -protected amino acid as a carboxylic acid component, Ugi intermediates could be cyclized from two possible directions to target 3,4-dihydropyrazin-2(1)-ones.

Isocyanide Multicomponent Reactions on Solid Phase: State of the Art and Future Application.

Drug discovery efforts largely depend on access to structural diversity. Multicomponent reactions allow for time-efficient chemical transformations and provide advanced intermediates with three or four points of diversification for further expansion to a structural variety of organic molecules. This review is aimed at solid-phase syntheses of small molecules involving isocyanide-based multicomponent reactions.

Greening Solid-Phase Organic Synthesis: Environmentally Conscious Synthesis of Pharmaceutically Relevant Privileged Structures 5,6-Dihydropyridin-2(1)-ones and Quinolin-2(1)-ones.

Solid-phase organic synthesis (SPOS) is a very efficient methodology for the synthesis of diverse organic molecules, particularly exploited in drug discovery. Here, we present the transformation of the traditional SPOS to an eco-friendlier methodology on examples of pharmacologically relevant privileged structures 5,6-dihydropyridin-2(1)-ones and quinolin-2(1)-ones. The green approach is primarily based on the utilization of environmentally friendly solvent 2-MeTHF in all steps of the synthesis.

Environmentally Friendly SPPS II: Scope of Green Fmoc Removal Protocol Using NaOH and Its Application for Synthesis of Commercial Drug Triptorelin.

With the growing necessity to consider environmental impacts when synthesizing peptide-based drugs and to expand upon the recently published short communication report, we herein present a thorough evaluation of a green Fmoc removal protocol. Our protocol avoids the use of hazardous components (using piperidine as a base and dichloromethane (DCM) and ,-dimethylformamide (DMF) as solvents) and relies on the utilization of the green mineral base NaOH in combination with the greener solvent 2-methyltetrahydrofuran (2-MeTHF) mixed with MeOH. For the original Fmoc removal cocktail (solvents ratio of 1:1), we evaluated the impact of quality/purity of the used 2-MeTHF, scale-up, ratio of 2-MeTHF/MeOH, utilized hydroxide, temperature, and reaction time.

Traceless Solid-Phase Organic Synthesis.

Traceless solid-phase synthesis represents an ultimate sophisticated synthetic strategy on insoluble supports. Compounds synthesized on solid supports can be released without a trace of the linker that was used to tether the intermediates during the synthesis. Thus, the target products are composed only of the components (atoms, functional groups) inherent to the target core structure.

Deuteration of BTZ043 Extends the Lifetime of Meisenheimer Intermediates to the Antituberculosis Nitroso Oxidation State.

Substituted nitrobenzothiazinones (BTZs) are potent antituberculosis prodrugs that are reductively activated to produce nitroso moieties that form covalent adducts with a cysteine residue of decaprenylphosphoryl-β-d-ribose-2'-oxidase (DprE1) of (). The resulting cell wall synthesis inhibition is lethal to , leading to consideration of development of BTZs for clinical use. The hydride-induced reduction of the nitroaromatic proceeds by reversible formation of the corresponding Meisenheimer complex.

Traceless Solid-Phase Synthesis of Ketones via Acid-Labile Enol Ethers: Application in the Synthesis of Natural Products and Derivatives.

In solid-phase organic synthesis, Wang resin is traditionally used for the immobilization of acids, alcohols, phenols, and amines. We report the use of Wang resin for the traceless synthesis of ketones via acid-labile enol ethers. We demonstrate the practicality of this synthetic strategy on the solid-phase synthesis of pyrrolidine-2,4-diones, which represent the core structure of several natural products, including tetramic acid.

Application of Glaser-Hay Diyne Coupling To Constrain N-Amino Acid Amides via a N-N Bridge.

We present the application of a Glaser-Hay diyne coupling for the synthesis of conformationally constrained N-amino acid amides with different diyne ring sizes. Twelve-membered rings were the smallest rings that could be prepared by this approach. We observed the formation of triethylammonium adducts in the cases of smaller (10- and 11-membered) rings.

Configuration-Dependent Medium-Sized Ring Formation: Chiral Molecular Framework with Three-Dimensional Architecture.

This report describes a configuration-dependent [6 + 8 + 5] fused ring formation via a tandem cyclic N-acyliminium nucleophilic addition reaction. Cyclization of the acyclic precursor prepared on a solid phase using l-Ser and a racemic mixture of Fmoc- trans-2-aminocyclohexanecarboxylic acid predominantly yielded the cyclic diastereomer with the (1 R,2 R)-2-aminocyclohexane moiety rather than the tricyclic diastereomer from the (1 S,2 S)-enantiomer. In contrast, the model compound prepared with d-Ser predominantly cyclized with the (1 S,2 S)-2-aminocyclohexanecarboxylic acid substrate.

Traceless Solid-Phase Synthesis of 1' H-Spiro[Pyrrolidine-3,2'-quinazolin]-2-ones and 1' H-Spiro[Piperidine-3,2'-quinazolin]-2-ones via Lactamization of 1,2-Dihydroquinazoline-2-carboxylates.

We present the solid-phase synthesis of 1,2-dihydroquinazoline-2-carboxylate derivatives with a quaternary carbon in position 2 and their subsequent cyclization in solution into compounds with unique 3D architectures and pharmacological relevance-spiroquinazolines, namely, 1' H-spiro[pyrrolidine-3,2'-quinazolin]-2-ones and 1' H-spiro[piperidine-3,2'-quinazolin]-2-ones. Acyclic precursors were prepared from commercially available building blocks: protected amino acids (2,4-diaminobutyric acid and ornithine), 2-nitrobenzensulfonyl chlorides and α-bromoacetophenones. The crucial step of the synthesis was a base-mediated tandem reaction including C-arylation followed by cyclization into indazole oxides, and the formation of a 5-membered heterocycle was accomplished by ring expansion into quinazolines.

N-Amino acid containing privileged structures: design, synthesis and use in solid-phase peptide synthesis.

Fmoc-protected Nα-amino acid containing heterocyclic privileged structures, O-(1-methyl-5-oxo-2,5-dihydro-1H-pyrrol-3-yl)-l-serine and O-((S)-5-oxo-2,3,5,7a-tetrahydro-1H-pyrrolizin-7-yl)-l-serine, were synthesized on the solid phase from simple commercially available building blocks under mild conditions. The amino acid side-chain is composed of tetramic acid, a natural product derived privileged structure. The key transformation was the formation of cyclic enol ethers via nonclassical Wittig olefinations of the esters.

Traceless Solid-Phase Synthesis of [6,7,8 + 5,6,7]-Fused Molecular Frameworks.

We report two synthetic strategies for traceless solid-phase synthesis of molecular scaffolds comprising 6- to 8-membered rings fused with 5- to 7-membered rings. Traceless synthesis facilitated preparation of target molecules without any trace of polymer-supported linkers. The cyclization proceeded via acid-mediated tandem -acylium ion formation followed by the nucleophilic addition of - and -nucleophiles.

Gold-Catalyzed Solid-Phase Synthesis of 3,4-Dihydropyrazin-2(1H)-ones: Relevant Pharmacophores and Peptide Backbone Constraints.

Here, we report the efficient solid-phase synthesis of N-propargyl peptides using Fmoc-amino acids and propargyl alcohol as key building blocks. Gold-catalyzed nucleophilic addition to the triple bond induced C-N bond formation, which triggered intramolecular cyclization, yielding 1,3,4-trisubstituted-5-methyl-3,4-dihydropyrazin-2(1H)-ones. Conformations of acyclic and constrained peptides were compared using a two-step conformer distribution analysis at the molecular mechanics level and density functional theory.

Traceless Solid-Phase Synthesis of Fused Chiral Macrocycles via Conformational Constraint-Assisted Cyclic Iminium Formation.

Natural products comprising chiral molecular scaffolds containing fused medium-sized cycles and macrocycles represent an important and relevant pharmacological target for the discovery and development of new drugs. Here, we describe traceless solid-phase synthesis of acyclic intermediates amenable to cyclization to medium (11) and large (12) fused rings. The key aspect of the synthetic strategy is incorporation of a specific conformation constraint that facilitates cyclization in favor of 11- and 12-membered rings rather than possible 7-membered ones.

In Vivo Dearomatization of the Potent Antituberculosis Agent BTZ043 via Meisenheimer Complex Formation.

Nitrobenzothiazinones are among the most potent antituberculosis agents. Herein, we disclose an unprecedented in vivo reduction process that affords Meisenheimer complexes of the clinical candidates BTZ043 and PBTZ169. The reduction is reversible, occurs in all mammalian species investigated, has a profound influence on the in vivo ADME characteristics, and has considerable implications for the design and implementation of clinical studies.

Fused Ring Molecular Scaffold with 3D Architecture for Constrained Peptidomimetics: Polymer-Supported Stereoselective Synthesis of Tetrahydrobenzo[e]pyrazino[2,1-c][1,2,4]thiadiazinone 6,6-dioxide via N-Acyl Iminiums.

3,4,4a,5-Tetrahydrobenzo[e]pyrazino[2,1-c][1,2,4]thiadiazin-1(2H)-one 6,6-dioxides, molecular scaffolds with 3D architecture, were synthesized on solid supports via tandem N-acyl iminium ion cyclization followed by nucleophilic addition. The modular synthesis proceeded under mild conditions using commercially available building blocks and provided crude products with respectable purity. The synthesized compounds are applicable as fused nitrogenous heterocyclic compounds in drug discovery and as constrained peptidomimetics incorporated into a peptide backbone.

Synthesis of a Small Library of Imidazolidin-2-ones using Gold Catalysis on Solid Phase.

An efficient and high-yielding solid phase synthesis of a small library of imidazolidin-2-ones and imidazol-2-ones was carried out employing a high chemo- and regioselective gold-catalyzed cycloisomerization as a key step. Polymer-supported amino acids derivatized with several alkyne functionalities combined with tosyl- and phenylureas have been subjected to gold-catalysis exhibiting exclusively C-N bond formation. The present work proves the potential of solid phase synthesis and homogeneous gold catalysis as an efficient and powerful synthetic tool for the generation of drug-like heterocycles.

N-Oxide as an Intramolecular Oxidant in the Baeyer-Villiger Oxidation: Synthesis of 2-Alkyl-2H-indazol-3-yl Benzoates and 2-Alkyl-1,2-dihydro-3H-indazol-3-ones.

In this study, we describe the intramolecular Baeyer-Villiger oxidation of ketones to esters using N-oxide. 2-Nitro-N-alkyl-N-(2-oxo-2-phenylethyl)benzenesulfonamide compounds are known to undergo base-mediated C-arylation followed by N-N bond formation, producing unstable five-membered ring intermediates that spontaneously dehydrate to indazole oxides. We identified the reaction conditions under which the cyclic intermediate undergoes acid-mediated intramolecular Baeyer-Villiger oxidation of the ketone in which N-oxide serves as the intramolecular oxidizing agent.

Synthesis of Nature-Inspired Medium-Sized Fused Heterocycles from Amino Acids.

Herein, we describe the synthesis of molecular scaffolds consisting of medium-sized fused heterocycles using amino acids, which are some of the most useful building blocks used by nature as well as chemists to create structural diversity. The acyclic precursors were assembled by using traditional Merrifield solid-phase peptide synthesis, and cyclization was carried out through acid-mediated tandem endocyclic N-acyliminium ion formation, followed by nucleophilic addition with internal nucleophiles. The synthesis of molecular scaffolds consisting of seven-, eight-, and nine-membered rings proceeded with full stereocontrol of the newly generated stereogenic center in most cases.

3-Alkyl-3-(alkylamino)indolin-2-ones via Base-Mediated C-Arylation of 2-Nitrobenzenesulfonamides.

Resin-bound intermediates prepared from polymer-supported amino acid esters, 2-nitrobenezenesulfonyl chlorides, and alcohols were used to synthesize 3-alkyl-3-(alkylamino) indolin-2-ones. The key step of the reaction sequence was the formation of a quaternary carbon via the base-mediated C-arylation of 2-nitrobenzenesulfonamides. The cleavage of the acyclic precursors from the resin and subsequent reduction of the nitro group by Zn in acetic acid triggered the spontaneous cyclization of the arylated compounds to indolinones.

Traceless Solid-Phase Synthesis of Trisubstituted Quinazolines.

A traceless polymer-supported synthesis of 4-benzoylquinazolines was developed using the following commercially available building blocks: Fmoc-α-amino acids, 2-nitrobenzensulfonyl chlorides and α-bromoacetophenones. The acyclic intermediates underwent base-catalyzed rearrangement involving C-C and N-N bond formation followed by ring expansion and yielded resin-bound dihydroquinazoline-2-carboxylic acids. After they were released from the resin by treatment with trifluoroacetic acid, base-mediated decarboxylation produced the target quinazolines in moderate-to-high yields and purities.

Ring contraction of 2,5-dihydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxides: access to 4H-benzo[b][1,4]thiazine 1,1-dioxides.

We report an efficient synthesis of 4H-benzo[b][1,4]thiazine 1,1-dioxides via unprecedented ring contraction of 2,5-dihydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxides under mild conditions involving carbon-sulfur bond formation. 2,5-Dihydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxides are easily accessible from commercially available building blocks, including Fmoc-protected amino acids, 2-nitrobenzenesulfonyl chlorides, and bromo ketones. Benzothiazine 1,1-dioxides represent pharmacologically relevant derivatives with biological, medicinal, and industrial applications.

Solid-phase synthesis of 2-aryl-3-alkylamino-1H-indoles from 2-nitro-N-(2-oxo-2-arylethyl)benzenesulfonamides via base-mediated C-arylation.

Polymer-supported 2-nitro-N-(2-oxo-2-arylethyl)benzenesulfonamides, prepared from resin-bound amines by sulfonylation with 2-nitrobenzenesulfonyl chlorides followed by alkylation with α-bromoacetophenones, represent advanced intermediates for the synthesis of different nitrogenous heterocycles. We report their application for the synthesis of 2-aryl-3-alkylamino-1H-indoles via base-mediated C-arylation reactions followed by the reduction of the C-arylated intermediates. Linear precursors for C-arylation were prepared on solid-phase support from simple, commercially available building blocks.

From amino acids to nature-inspired molecular scaffolds: incorporation of medium-sized bridged heterocycles into a peptide backbone.

Novel molecular scaffolds comprising two to four bridged and fused heterocycles were synthesized from amino acids using seven-membered endocyclic N-acyliminium ions as key intermediates in acid-mediated tandem reactions with internal nucleophiles. This complexity-generating synthesis proceeds with high efficiency and with full stereocontrol of the newly generated stereogenic center. These results have extended the scope of medium-sized cyclic iminium ion chemistry, making it applicable as a regio- and stereoselective synthetic strategy for the generation of complex polycyclic structures.

Benzhydrylamines via base-mediated intramolecular sp(3) C-arylation of N-benzyl-2-nitrobenzenesulfonamides--advanced intermediates for the synthesis of nitrogenous heterocycles.

N-Benzyl-2-nitrobenzenesulfonamides underwent base-mediated intramolecular arylation at the benzyl sp(3) carbon to yield benzhydrylamines. The presence of electron withdrawing groups on the aromatic ring of the benzyl group was required to facilitate the C-arylation. Unsymmetrically substituted benzhydrylamines are advanced intermediates toward nitrogenous heterocycles, as exemplified in the syntheses of indazole oxides and quinazolines.