N-Boc Deprotection Research Articles

Selective Thermal Deprotection of N-Boc Protected Amines in Continuous Flow.

Thermal N-Boc deprotection of a range of amines is readily effected in continuous flow, in the absence of an acid catalyst. While the optimum results were obtained in methanol or trifluoroethanol, deprotection can be effected in a range of solvents of different polarities. Sequential selective deprotection of N-Boc groups has been demonstrated through temperature control, as exemplified by effective removal of an aryl N-Boc group in the presence of an alkyl N-Boc group. As a proof of principle, a telescoped sequence involving selective deprotection of an aryl N-Boc group from 9h followed by benzoylation and deprotection of the remaining alkyl N-Boc group to form amide 13 proved successful.

Optimized Synthesis of a Key Intermediate of Nirmatrelvir

In this study, the development of a concise alternative process for synthesis of a key nirmatrelvir intermediate cyclic glutamine analog is described. The process proceedes via α-cyanomethylation of dimethyl N-BocGlu in the presence of NdCl3, followed by one-pot Raney nickel-catalyzed hydrogenation of the cyano group with concomitant cyclization and ammonolysis and subsequent deprotection of N-Boc to deliver the target intermediate cyclic glutamine analog in three steps with an 82% overall yield and 99.4 A% high-performance liquid chromatography (HPLC) purity. This study resulted in improved synthetic efficiency and stereoselectivity of α-cyanomethylation for production of a key nirmatrelvir intermediate cyclic glutamine analog.

A Brønsted Acidic Deep Eutectic Solvent for N-Boc Deprotection

The tert-butyloxycarbonyl (Boc) group is one of the most widely used amine-protecting groups in multistep reactions in synthetic organic chemistry as well as in peptide synthesis. Traditional methods to remove the Boc group have disadvantages in terms of high acidity, the use of expensive reagents, excessive amounts of catalysts and harmful solvents as well as high temperatures, making them environmentally unsustainable. Therefore, more efforts must be stepwise tightened to make Boc removal practical, clean, and minimize any potential impact. We describe an efficient and sustainable method for N-Boc deprotection by means of a choline chloride/p-toluenesulfonic acid deep eutectic solvent (DES), which is used as a reaction medium plus catalyst. The adopted conditions allow the deprotection of a wide variety of N-Boc derivatives in excellent yields. The strategy has found advantages in greening, simplicity, and short reaction times, resulting in a useful alternative to standard methods.

Facile and Efficient N-Boc Deprotection of Amide and Sulfonamide under Microwave Irradiation in Water

Facile and Efficient N-Boc Deprotection of Amide and Sulfonamide under Microwave Irradiation in Water

Meso-scale surface patterning of self-assembled monolayers with water

We developed an experimentally simple method for localized N-tert-butyloxycarbonyl amino group (N-Boc) deprotection on surface applicable to meso-scale on-demand patterning for further synthetic modifications. The chemical patterning is accomplished on heated self-assembled monolayers using micro-drop equipment and water as the sole chemical.

Biological Activity and Molecular Docking Study of Some Bicyclic Structures: Antidiabetic and Anticholinergic Potentials

Bicyclic structures were synthesized by LACASA-DA cycloaddition reaction using (S)-BINOL as a chiral inductor. The N-2 pyridazine position was protected; the hydroxyl group was carbonylated to form the new bicyclic structure. The protective group was removed, the double bond dehydroxylated leading to the target compound. Removing of the protective group was performed using newly found ecofriendly catalyst for N-Boc deprotection. The obtained features from the model against AChE enzyme suggest that a lower the size of the ring, number of –NH-NH- groups, number of secondary aromatic amines, number of aromatic ketone groups may contribute to the inhibitory activity. The features obtained from the model against BChE enzyme suggest that the sum of topological distances between two nitrogen atoms, number of secondary aromatic amides, may be more favorable for inhibition. The features obtained from selectivity-based model suggest that the number of aromatic ethers, unsaturation content related to their molecular size and molecular shape may be more specific for the inhibition of the AChE enzyme in comparison to the BChE enzyme. Similarly, these aromatic structures inhibited the α-glucosidase enzyme at the micromolar level due to its structural feature. Inhibition values were found to be statistically significant, especially for cholinesterase enzymes. Molecular docking method was used to compare the biological activities of molecules against enzymes. The enzymes used in this study are α-glycosidase, butyrylcholinesterase, acetylcholinesterase, respectively. ADME/T analysis was performed to use some bicyclic molecules as drugs in the future.

Diastereoselective, Multicomponent Synthesis of Pyrrolopyrazinoquinazolinones via a Tandem Quinazolinone Rearrangement/Intramolecular Ring Closure of Tautomeric (Z)-Benzamidines.

An expedient route to enantiopure, diastereomeric pyrrolopyrazinoquinazolinones was developed following the discovery of a domino quinazolinone rearrangement-intramolecular cyclization of N-H benzamidines. A Ugi-Mumm-Staudinger sequence employing an optically pure proline derivative gave quinazolinones that, upon N-Boc deprotection, rearranged to tautomeric Z-benzamidines. Subsequent spontaneous cyclization afforded 15 diastereomeric pyrazinoquinazolinone pairs in up to 83% overall yield and 89:11 d.r which were separated easily via routine chromatographic purification-the only one required in the entire process.

Synthesis of Computationally Designed 2,5(6)-Benzimidazole Derivatives via Pd-Catalyzed Reactions for Potential E. coli DNA Gyrase B Inhibition.

A pharmacophore model for inhibitors of Escherichia coli’s DNA Gyrase B was developed, using computer-aided drug design. Subsequently, docking studies showed that 2,5(6)-substituted benzimidazole derivatives are promising molecules, as they possess key hydrogen bond donor/acceptor groups for an efficient interaction with this bacterial target. Furthermore, 5(6)-bromo-2-(2-nitrophenyl)-1H-benzimidazole, selected as a core molecule, was prepared on a multi-gram scale through condensation of 4-bromo-1,2-diaminobenzene with 2-nitrobenzaldehyde using a sustainable approach. The challenging functionalization of the 5(6)-position was carried out via palladium-catalyzed Suzuki–Miyaura and Buchwald-Hartwig amination cross-coupling reactions between N-protected-5-bromo-2-nitrophenyl-benzimidazole and aryl boronic acids or sulfonylanilines, with yields up to 81%. The final designed molecules (2-(aminophen-2-yl)-5(6)-substituted-1H-benzimidazoles), which encompass the appropriate functional groups in the 5(6)-position according to the pharmacophore model, were obtained in yields up to 91% after acid-mediated N-boc deprotection followed by Pd-catalyzed hydrogenation. These groups are predicted to favor interactions with DNA gyrase B residues Asn46, Asp73, and Asp173, aiming to promote an inhibitory effect.

Efficient, continuous N-Boc deprotection of amines using solid acid catalysts

Rapid, catalytic N-Boc deprotection of aromatic and aliphatic amines is achieved using readily-available porous inorganic solid acids in flow.

Efficient synthesis of piperazinyl amides of 18β-glycyrrhetinic acid.

In the present study, a practical method to prepare piperazinyl amides of 18β-glycyrrhetinic acid was developed. Two main procedures for the construction of important intermediate 8 are discussed. One procedure involves the amidation of 1-Boc-piperazine with 3-acetyl-18β-glycyrrhetinic acid, prepared by the reaction of 18β-glycyrrhetinic acid with acetic anhydride without any solvent at 130 °C. The other procedure to prepare compound 8 involves the amidation of 18β-glycyrrhetinic acid followed by the esterification with acetic anhydride. Finally, compound 8 underwent N-Boc deprotection to prepare product 4. To ascertain the scope of the reaction, another C-3 ester derivative 17 was tested under the optimized reaction conditions. Furthermore, the reasons for the appearance of byproducts were elucidated. Crystallographic data of a selected piperazinyl amide is reported.

An Acid-Catalyzed Epoxide Ring-Opening/Transesterification Cascade Cyclization to Diastereoselective Syntheses of (±)-β-Noscapine and (±)-β-Hydrastine.

An acid-catalyzed stereoselective epoxide ring-opening/intramolecular transesterification cascade cyclization reaction and N-Boc deprotection was found to be a successful strategy to construct the phthalide tetrahydroisoquinoline skeleton in one pot. Based on this strategy, the unified and highly diastereoselective routes for the total syntheses of (±)-β-Noscapine and (±)-β-Hydrastine were exploited.

A biodegradable poly(amido amine) based on the antimicrobial polymer polyhexamethylene biguanide for efficient and safe gene delivery

Inspired by the excellent membrane affinity of antimicrobial polymers, we synthesized a novel biodegradable poly(amino amine) polymer with pendent side chains that mimic the widely used biocide polyhexamethylene biguanide (PHMB) for gene delivery. Michael addition polymerization was utilized to form the polymer scaffold between N,N′-cystaminebisacrylamide (CBA) and N-Boc-1,6-diaminohexane (Boc-DAH) followed by N-Boc deprotection. Then the exposed primary amino groups were partly (about 75%) transformed into biguanide by an addition reaction with dicyandiamide to obtain the final product CBA-DAH-biguanide (CBA-DAH-BG). The polymer CBA-DAH-BG was able to condense plasmid DNA (pDNA) into nano-sized (<200 nm), positively-charged (>35 mV) polyplexes that were well resistant to heparin and DNase I. Rapid DNA release was observed in the presence of dithiothreitol (DTT), indicating that CBA-DAH-BG was equipped with biodegradability by the cleavage of disulfide bonds, which was helpful for unpacking DNA and decreasing cytotoxicity. CBA-DAH-BG/pDNA polyplexes were characterized by efficient cellular uptake efficacy, extremely low cytotoxicity, and high transfection efficiency in two cell lines (i.e., NIH/3T3 and U87 MG), compared to 25 kDa polyethyleneimine (PEI) and the intermediate product CBA-DAH that were both devoid of biguanide groups. Of note, clathrin-mediated endocytosis and lipid rafts played an important role in the internalization of the polyplexes. Taken together, this strategy described herein may represent an innovative avenue for the design of more advanced nonviral gene vectors with high transfection efficiency and biocompatibility.

Deprotection of N-Boc Groups under Continuous-Flow High-Temperature Conditions.

The scope of thermolytic, N-Boc deprotection was studied on 26 compounds from the Pfizer compound library, representing a diverse set of structural moieties. Among these compounds, 12 substrates resulted in clean (≥95% product) deprotection, and an additional three compounds gave ≥90% product. The thermal de-Boc conditions were found to be compatible with a large number of functional groups. A combination of computational modeling, statistical analysis, and kinetic model fitting was used to support an initial, slow, and concerted proton transfer with release of isobutylene, followed by a rapid decarboxylation. A strong correlation was found to exist between the electrophilicity of the N-Boc carbonyl group and the reaction rate.

Tertiary-butoxycarbonyl (Boc) – A strategic group for N-protection/deprotection in the synthesis of various natural/unnatural N-unprotected aminoacid cyanomethyl esters

A number of cyanomethyl esters of natural/unnatural aminoacids with un-protected amino functionality were synthesized because of their synthetic and medicinal importance. Critical N-Boc deprotection methods in the presence of labile (hydrolytic sensitivity) cyanomethyl functionality were screened thoroughly and it was found that readily available 4M HCl in 1,4-dioxane solution (2–4 equiv); acetonitrile, 0 °C, 2–4 h was a suitable condition. This condition was generalized and successfully applied to a variety of alkyl, alkynyl, aryl, heteroaryl, benzyl, azido, spiro amino acid cyanomethylesters irrespective of the nature of the amine (primary or secondary) and the distance between the amine and ester group to achieve final deprotected amino esters with high yield, and purity compared to other commonly known N-protecting groups (Cbz, Fmoc, Ac, Bn, Bz etc.). It was also demonstrated that N-Boc protected aminoacid cyanomethylesters are stable enough to carry out further functionalization compared to N-unprotected counterparts.

An optimised synthesis of SG3376, a non-cleavable antibody-drug conjugate pyrrolobenzodiazepine drug-linker

In recent years, antibody-drug conjugates (ADCs) have been evaluated in a growing number of clinical trials. Preclinical evaluation and the synthetic accessibility of cleavable pyrrolobenzodiazepine drug-linkers, such as talirine and tesirine, have been previously described. This article details how the synthesis of SG3376, a non-cleavable pyrrolobenzodiazepine drug-linker, has been optimised to provide access to late-stage versatile intermediates in a robust and scalable fashion. Of particular importance was the selective deprotection of primary N-Boc in the presence of secondary N-Boc and secondary O-TBS. SG3376 was conjugated to trastuzumab and the resulting ADC was found to have potent cytotoxic activity in a number of HER2-positive cancer cell lines.

Facile new industrial process for synthesis of teneligliptin through new intermediates and its optimization with control of impurities

The present study is related to a commercially practicable new synthetic process for production of teneligliptin hydrobromide hydrate (1), a dipeptidyl peptidase-4 (DPP-4) inhibitor. Key strategies in the new process include preparation and isolation of new intermediates such as a better reactive nosyl derivative (3c) of l-proline methyl ester (2), its stereoselective substituted intermediate (5) with 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (4) through SN2-type nucleophilic substitution, and isolation of carboxylic acid derivative 6 by deesterification of intermediate 5. The reaction conditions for preparation of new intermediates, and the additionally used coupling reaction for amidation and deprotection of N-Boc were optimized with control of impurities to improve the quality of drug molecule 1 with good yield. The developed synthetic strategy offers significant advantages over existing synthetic approaches, avoiding use of expensive reagents, long time consumption, and laborious procedures involving isolation of intermediates. The developed process for drug molecule 1, achieving overall yield of 37–39% over six sequential chemical transformations, enables rapid delivery of multi-kilogram quantities of the desired active pharmaceutical ingredient (API), meeting stringent purity requirements.

One-Pot N-Deprotection and Catalytic Intramolecular Asymmetric Reductive Amination for the Synthesis of Tetrahydroisoquinolines.

A one-pot N-Boc deprotection and catalytic intramolecular reductive amination protocol for the preparation of enantiomerically pure tetrahydroisoquinoline alkaloids is described. The iodine-bridged dimeric iridium complexes displayed superb stereoselectivity to give tetrahydroisoquinolines, including several key pharmaceutical drug intermediates, in excellent yields under mild reaction conditions. Three additives played important roles in this reaction: Titanium(IV) isopropoxide and molecular iodine accelerated the transformation of the intermediate imine to the tetrahydroisoquinoline product; p-toluenesulfonic acid contributed to the stereocontrol.

One-Pot Approach to N-Quinolyl 3'/4'-Biaryl Carboxamides by Microwave-Assisted Suzuki-Miyaura Coupling and N-Boc Deprotection.

N-Quinolyl biaryl carboxamides have received tremendous attention for their notable biological properties. Here we have described a general protocol for the preparation of N-quinolyl 3'/4'-biaryl carboxamides by microwave-assisted Suzuki-Miyaura cross-coupling reaction and N-Boc deprotection in one pot. This method, which did not require acids, was used to produce a series of N-quinolyl 3'/4'-biaryl carboxamides with excellent functional group tolerance and high yields (70% to 95%).

Concise and highly stereoselective syntheses of d-fagomine and 2-epi-fagomine

Highly stereoselective total syntheses of polyhydroxylated piperidines d-fagomine and 2-epi-fagomine have been developed starting from 3,4,6-tri-O-benzyl-d-glucal which is a derivative of d-Glucose. Key steps in the synthesis of these azasugars involved N-Boc-protected amine preparation from oxime followed by stereo specific iodination of alcohol and cascade cyclization triggered by N-Boc deprotection.

One-pot synthesis of a natural product inspired pyrrolocoumarine compound collection by means of an intramolecular 1,3-dipolar cycloaddition as key step

A general, sequential and efficient one-pot synthesis of natural product inspired chromeno[3,4-b]pyrrol-4(3H)-ones is described. The one-pot reaction sequence consists of N-Boc deprotection of a N-substituted Boc-glycine O-aryl ester embodying an ortho-alkyne substituent, azomethine ylide generation with an aldehyde, subsequent intramolecular 1,3-dipolar cycloaddition with the alkyne followed by oxidative aromatization. This synthesis method gives efficient access to a collection of highly substituted diverse pyrrolocoumarines.