Regioselective Cyclic Iminium Formation of Ugi Advanced Intermediates: Rapid Access to 3,4-Dihydropyrazin-2(1H)-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 N-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 N-protected amino acid as a carboxylic acid component, Ugi intermediates could be cyclized from two possible directions to target 3,4-dihydropyrazin-2(1H)-ones. Cyclization to the amino terminus (westbound) and to the carboxyl terminus (eastbound) was demonstrated. Deliberate selection of building blocks drove the reaction regioselectively and yielded diverse heterocycles containing a 3,4-dihydropyrazin-2(1H)-one core, pyrazin-2(1H)-one, and piperazin-2-one, as well as a tricyclic framework with a 3D architecture, 2,3-dihydro-2,6-methanobenzo[h][1,3,6]triazonine-4,7(1H,5H)-dione, from Ugi adducts under mild reaction conditions. The latter bridged heterocycle was achieved diastereoselectively. The reported chemistry represents diversity-oriented synthesis. One common Ugi advanced intermediate was, without isolation, rapidly transformed into various nitrogen-containing heterocycles.

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. The majority of all reported syntheses employ the Ugi four-component reaction. The review also covers the Passerini and Groebke-Blackburn-Bienaymé reactions. To date, the main advantages of the solid-phase approach are the ability to prepare chemical libraries intended for biological screening and elimination of the isocyanide odor. However, the potential of multicomponent reactions has not been fully exploited. The unexplored avenues of these reactions, including chiral frameworks, DNA-encoded libraries, eco-friendly synthesis, and chiral auxiliary reactions, are briefly outlined.

Greening Solid-Phase Organic Synthesis: Environmentally Conscious Synthesis of Pharmaceutically Relevant Privileged Structures 5,6-Dihydropyridin-2(1H)-ones and Quinolin-2(1H)-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(1H)-ones and quinolin-2(1H)-ones. The green approach is primarily based on the utilization of environmentally friendly solvent 2-MeTHF in all steps of the synthesis. Target heterocycles were synthesized by extending our previously published synthesis of five-membered tetramic acid analogues to six-membered cycles. The crucial step of the synthesis is cyclization via nonclassical Wittig olefination of resin-bound esters. Traditional and green protocols provided comparable results with respect to purity and yield of products, thus opening the way for greener access to a variety of diverse heterocycles.

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 N,N-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. An alternative 3:1 protocol was examined using various amino acids, and only Gly required the optimization of the Fmoc removal cocktail composition. The optimized protocol used to remove Fmoc from Gly residue was proved by the synthesis of Leu-enkephalin. We also investigated the stability of the conventional amino acid side-chain-protecting groups, t-Bu, Boc, Trt, and Pbf, and the formation of aspartimide as an undesirable side reaction that occurs during Fmoc solid-phase peptide synthesis (SPPS). The applicability of this synthesis strategy was documented by evaluating the SPPS of a commercial drug used for prostate and breast cancer treatments-decapeptide triptorelin.

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. A wide variety of synthetic strategies have been developed to prepare products in a traceless manner, and this review is dedicated to all aspects of traceless solid-phase organic synthesis. Importantly, the synthesis does not need to be carried out on a linker designed for traceless synthesis; most of the synthetic approaches described herein were developed using standard, commercially available linkers (originally devised for solid-phase peptide synthesis). The type of structure prepared in a traceless fashion is not restricted. The individual synthetic approaches are divided into eight sections, each devoted to a different methodology for traceless synthesis. Each section consists of a brief outline of the synthetic strategy followed by a description of individual reported syntheses.

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-ß-d-ribose-2'-oxidase (DprE1) of Mycobacterium tuberculosis (Mtb). The resulting cell wall synthesis inhibition is lethal to Mtb, 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. Herein we demonstrate that chemical reduction of BTZ043 with NaBD4 followed by reoxidation incorporates deuterium into the core nitro aromatic warhead. Subsequent reduction of the deuterated species is not affected, but, as expected, reoxidation is slowed by the deuterium isotope effect, thus prolonging the lifetime of the active nitroso oxidation state.

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. Base-triggered condensation of pyrrolidine-2,4-diones yielded 4-hydroxy-1,1',2',5-tetrahydro-2H,5'H-[3,3'-bipyrrole]-2,5'-diones.

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

We present the application of a Glaser-Hay diyne coupling for the synthesis of conformationally constrained Nα-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. Calculation of the conformational barriers for the cyclization reactions of various ring sizes demonstrated that the formation of amino acid-derived smaller rings by this reaction is thermodynamically unfavorable.

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. These derivatives were cyclized into spiro compounds in solution after cleavage from the resin.

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. The outcome of the cyclization was not influenced by the type of resin, the spacer, or the N-substituent. The analogous synthesis of the [6 + 7 + 5] fused ring system yielded inseparable diastereomers in a 1:0.6 ratio.

Nα-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. Solid-phase synthesis represents a method of choice, particularly for the synthesis of peptides. This route is compatible with traditional Merrifield solid-phase peptide synthesis (SPPS), as documented on the preparation of the pentapeptide Leu-enkephalin amide H-Tyr-Gly-Gly-Phe-Leu-NH2 with Phe or Tyr replaced by a novel amino acid.

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 N-acylium ion formation followed by the nucleophilic addition of O- and C-nucleophiles. The presented synthetic strategy enabled, through the use of simple building blocks without any conformational preferences, the evaluation of the predisposition of different combinations of ring sizes to form fused ring molecular scaffolds. Compounds with any combination of [6,7 + 5,6,7] ring sizes were accessible with excellent crude purity. The 8-membered cyclic iminium was successfully fused only with the 5-membered cycle and larger fused ring systems were not formed, probably due to their instability.

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. The results indicated that the incorporation of heterocyclic molecular scaffold into a short peptide sequence adopted extended conformation of peptide chain. The amide bond adjacent to the constraint did not show significant preference for either cis or trans isomerism. Prepared model compounds demonstrate a proof of concept for gold-catalyzed polymer-supported synthesis of variously substituted 3,4-dihydropyrazin-2(1H)-ones for applications in drug discovery and peptide backbone constraints.

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. The role of constraints in preorganization required for cyclization is supported by computational analysis. The synthesis involves cyclic N-sulfonyliminium-nucleophilic addition chemistry as the key ring-forming reaction and proceeds with complete stereocontrol of the newly formed stereogenic center. We document the scope and limitations of this strategy in the synthesis of 11+5, 11+6, 11+7, and 12+6 fused rings representing molecular scaffolds with 3D architecture that mimic complex natural products.

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. The reduction was confirmed by chemical studies that enabled the complete characterization of the Meisenheimer complex and its subsequent chemistry. Combination of the in vivo and chemical studies with LC-MS characterization and assay development also provides a basis for rational lead optimization of this very promising class of antituberculosis agents.

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. The solid-phase synthesis plays a critical role in the successful transformation, allowing rapid access to the unstable but Baeyer-Villiger oxidation-prone intermediate. This synthetic route provides practical access to 2-alkyl-2H-indazol-3-yl benzoates and 2-alkyl-1,2-dihydro-3H-indazol-3-ones, which are known privileged structures possessing remarkable diverse pharmacologically relevant activities.

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.

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. The synthesis was carried out using simple commercially available building blocks under mild conditions and provided the 3,3-disubstituted indolinone derivatives with good overall yields however, the arylation reaction resulted in the epimerization of the quaternary carbon.