Protecting-Group-Free Synthesis of ADP-Ribose and Dinucleoside Di-/Triphosphate Derivatives via P(V)-P(V) Coupling Reaction.

Biomolecules containing adenosine di- or triphosphate (ADP or ATP) are crucial for diverse biological processes. Synthesis of these biomolecules and development of their chemical probes are important to elucidate their functions. Enabling reproducible and high-yielding access to these ADP- and ATP-containing molecules via conventional P(III)-P(V) and P(V)-P(V) coupling reactions is challenging owing to water content in highly polar phosphate-containing substrates. Herein, we report an efficient and reliable method for protecting-group-free P(V)-P(V) coupling reaction through in situ activation of phosphates using hydrolysis-stable 2-[N-(2-methylimidazoyl)]-1,3-dimethylimidazolinium chloride (2-MeImIm-Cl), providing the corresponding electrophilic P(V) intermediates for subsequent nucleophilic attack using their coupling partners. This P(V)-P(V) coupling reaction proceeded even in a wet reaction medium and showed a broad substrate scope, accommodating protecting-group-free synthesis of ADP-ribose and nicotinamide adenine diphosphate analogs, ATP-containing biomolecules, and ADP-ribosyl peptides.

Stereoselective protecting-group-free synthesis of alkyl glycosides using dibenzyloxy triazine type glycosyl donors.

Chemical O-glycosylation is a key step for the synthesis of sugar-containing molecules such as glycolipids. However, traditional carbohydrate chemistry is characterized by extensive use of protective groups, resulting in laborious manipulations and poor atom economy. Here, we present a protecting-group-free glycosylation strategy employing dibenzyloxy-1,3,5-triazin-2-yl glycosides (DBT-glycosides) as glycosyl donors. The DBT-glycosyl donors could be prepared directly through an alkaline nucleophilic substitution from unprotected sugars in aqueous media. The O-glycosylation of alcohols by using DBT-glycosyl donors has been carried out under mild hydrogenolytic conditions, affording the corresponding alkyl glycosides stereo-selectively in good yields.

An Acid-Controlled Method for the Regioselective Functionalization of Anilines over Aliphatic Amines.

Regioselective transformations at similar functional groups are of paramount importance in organic synthesis. Traditional strategies towards regioselective functionalization include serial protection/deprotection and sequential synthesis. Modern organic synthesis emphasizes pathway efficiency and protecting group free routes with a goal of exploiting inherent differences in reactivity. This study reports a method for the regioselective functionalization of anilines over aliphatic amines. Utilizing classic conditions for the Baeyer-Mills reaction, anilines were shown to react preferentially in the presence of aliphatic amines. Subsequently, this principle of reactivity was extended to other electrophiles and conditions.

Synthesis of molnupiravir (MK-4482, EIDD-2801): a promising oral drug for the treatment of COVID-19 starting from cytidine.

The present work describes the synthesis of molnupiravir by employing commercially available inexpensive materials in two steps with an overall yield of 85.7%. The synthetic methodology starts with an eco-friendly starting material, that is, cytidine and establishes an alternative way to avoid costly enzyme mediated reactions. This synthetic strategy involves a selective acylation of cytidine as the first key step followed by the second step, that is, hydroxamination reaction. The major advantage of this protocol is that it is completely free of protection and deprotection reactions. Chemoselective acylation of cytidine's primary alcohol was achieved using isobutyryl chloride, Et3N, and DMF solvent (89.3% yield). The aqueous phase transformation was achieved for the hydroxamination reaction with a 96% yield.

Protecting-group- and microwave-free synthesis of ß-glycosyl esters and aryl ß-glycosides of N-acetyl-d-glucosamine.

A protecting-group-free method for synthesis of ß-glycosyl esters and aryl ß-glycosides was developed by using latent chemical reactivity of N-acetyl-d-glucosamine (GlcNAc) oxazoline. The GlcNAc oxazoline was spontaneously reacted with carboxylic acids and phenol derivatives via the oxazoline ring opening without the use of a catalyst or heating conditions (i.e., microwave irradiation), affording the desired products in moderate to excellent yields with ß-selectivity. This simple protecting-group-free method exhibits a wide substrate scope and good functional group tolerance, and it allows the efficient production of a novel class of GlcNAc-conjugated biomaterials and prodrug candidates.

1, 2-trans-Stereoselective 7-O-Glycosylation of Flavonoids with Unprotected Pyranoses by Mitsunobu Reaction.

The glycosylation of protecting-group-free pyranoses with flavonoids to generate flavonoid O-glycosides under Mitsunobu conditions was reported. The methodology allows to prepare a wide range of natural 7-flavonoid O-glycosides and their derivatives from commercially available chemicals in good to excellent yields with exclusive 1,2-trans-stereoselectivity regardless the anomeric configuration of employed pyranoses. The highly regioselective glycosylation was also achieved among different types of hydroxyl groups on the glycosyl acceptors.

Streamlined Iterative Assembly of Thio-Oligosaccharides by Aqueous S-Glycosylation of Diverse Deoxythio Sugars.

A streamlined iterative assembly of thio-oligosaccharides was developed by aqueous glycosylation. Facile syntheses of various deoxythio sugars with the sulfur on different positions from commercially available starting materials were described. These syntheses featured efficient chemical methods including our recently reported BTM-catalyzed site-selective acylation. The resulting deoxythio sugars could then be used for the Ca(OH)2 -promoted protecting group-free S-glycosylation in water at room temperature. The aqueous glycosylation reaction proceeded smoothly to afford the corresponding 1,2-trans S-glycosides in good yields with high chemo- and stereoselectivity. An appropriate choice of protecting groups for the thiol in the glycosyl donor was necessary for the development of iterative synthesis of thio-oligosaccharides. The aqueous glycosylation was then applied to the synthesis of a trimannoside moiety of N-linked glycans core region.

Facile Approach to C-Glucosides by Using a Protecting-Group-Free Hiyama Cross-Coupling Reaction: High-Yielding Dapagliflozin Synthesis.

Access to unprotected (hetero)aryl pseudo-C-glucosides via a mild Pd-catalysed Hiyama cross-coupling reaction of protecting-group-free 1-diisopropylsilyl-d-glucal with various (hetero)aryl halides has been developed. In addition, selected unprotected pseudo-C-glucosides were stereoselectively converted into the corresponding α- and ß-C-glucosides, as well as 2-deoxy-ß-C-glucosides. This methodology was applied to the efficient and high-yielding synthesis of dapagliflozin, a medicament used to treat type 2 diabetes mellitus. Finally, the versatility of our methodology was proved by the synthesis of other analogues of dapagliflozin.

Chemical (neo)glycosylation of biological drugs.

Biological drugs, specifically proteins and peptides, are a privileged class of medicinal agents and are characterized with high specificity and high potency of therapeutic activity. However, biologics are fragile and require special care during storage, and are often modified to optimize their pharmacokinetics in terms of proteolytic stability and blood residence half-life. In this review, we showcase glycosylation as a method to optimize biologics for storage and application. Specifically, we focus on chemical glycosylation as an approach to modify biological drugs. We present case studies that illustrate the success of this methodology and specifically address the highly important question: does connectivity within the glycoconjugate have to be native or not? We then present the innovative methods of chemical glycosylation of biologics and specifically highlight the emerging and established protecting group-free methodologies of glycosylation. We discuss thermodynamic origins of protein stabilization via glycosylation, and analyze in detail stabilization in terms of proteolytic stability, aggregation upon storage and/or heat treatment. Finally, we present a case study of protein modification using sialic acid-containing glycans to avoid hepatic clearance of biological drugs. This review aims to spur interest in chemical glycosylation as a facile, powerful tool to optimize proteins and peptides as medicinal agents.

Concise Syntheses of Violaceoids A and C.

The concise syntheses of two alkylated hydroquinone natural products, violaceoids A and C, were accomplished by a protecting-group-free method employing the commercially available 2,5-dihydroxybenzaldehyde as the starting material. The key strategy of the syntheses is the utilization of alkenylboronic acid as both the coupling and temporary protective reagents to efficiently introduce the requisite alkenyl side chain of violaceoid A. Moreover, the synthesis of violaceoid C is reported here for the first time.

Applications of Shoda's reagent (DMC) and analogues for activation of the anomeric centre of unprotected carbohydrates.

2-Chloro-1,3-dimethylimidazolinium chloride (DMC, herein also referred to as Shoda's reagent) and its derivatives are useful for numerous synthetic transformations in which the anomeric centre of unprotected reducing sugars is selectively activated in aqueous solution. As such unprotected sugars can undergo anomeric substitution with a range of added nucleophiles, providing highly efficient routes to a range of glycosides and glycoconjugates without the need for traditional protecting group manipulations. This mini-review summarizes the development of DMC and some of its derivatives/analogues, and highlights recent applications for protecting group-free synthesis.

A Versatile Method for Kinetic Resolution of Protecting-Group-Free BINAMs and NOBINs through Chiral Phosphoric Acid Catalyzed Triazane Formation.

A versatile kinetic resolution of protecting-group-free BINAMs and NOBINs has been realized through chiral phosphoric acid catalyzed triazane formation with azodicarboxylates. A series of mono-N-protected and unprotected BINAMs, diphenyl diamines and NOBIN derivatives could be kinetically resolved with excellent performances (with s factor up to 420). The gram-scale reactions and facile derivatizations of the chiral products demonstrate the potential of these methods in the asymmetric synthesis of chiral catalysts and ligands.

Design and Scalable Synthesis of N-Alkylhydroxylamine Reagents for the Direct Iron-Catalyzed Installation of Medicinally Relevant Amines*.

Secondary and tertiary alkylamines are privileged substance classes that are often found in pharmaceuticals and other biologically active small molecules. Herein, we report their direct synthesis from alkenes through an aminative difunctionalization reaction enabled by iron catalysis. A family of ten novel hydroxylamine-derived aminating reagents were designed for the installation of several medicinally relevant amine groups, such as methylamine, morpholine and piperazine, through the aminochlorination of alkenes. The method has excellent functional group tolerance and a broad scope of alkenes was converted to the corresponding products, including several drug-like molecules. Besides aminochlorination, the installation of other functionalities through aminoazidation, aminohydroxylation and even intramolecular carboamination reactions, was demonstrated, further highlighting the broad potential of these new reagents for the discovery of novel amination reactions.

Short Protecting Group-free Syntheses of CDE Synthon of Racemic Camptothecin.

A practical and concise total synthesis of tricyclic ketone 7 (CDE ring), a valuable intermediate for the synthesis of racemic camptothecin and analogs, was described (8 chemical steps and 29% overall yield). The synthesis starts with two inexpensive, readily available materials and is operationally simple to perform. It is worth mentioning that the reported protecting group-free synthesis, with advantages of a short route, would be helpful for the future development of industry-scale syntheses of camptothecin-family alkaloids.

Rapid, two-pot procedure for the synthesis of dihydropyridinones; total synthesis of aza-goniothalamin.

A fast, protecting-group-free synthesis of dihydropyridinones has been developed. Starting from commercially available aldehydes, a novel one-pot amidoallylation gave access to diene compounds in good yields. Ring-closing metathesis conditions were then employed to produce the target dihydropyridinones efficiently and in high yields.

Concise synthesis of (±)-litseaones A and B.

A concise synthesis of litseaones A and B, which were isolated from the stem barks of Litsea rubescens and L. pedunculata, is described in this study. Litseaone A was synthesized in just three steps from a known phloroglucinol derivative. The direct conversion of litseaone A into litseaone B was also achieved.

Facile chemoenzymatic synthesis of Lewis a (Lea) antigen in gram-scale and sialyl Lewis a (sLea) antigens containing diverse sialic acid forms.

An efficient streamlined chemoenzymatic approach has been developed for gram-scale synthesis of Lewis a angtigen (LeaßProN3) and a library of sialyl Lewis a antigens (sLeaßProN3) containing different sialic acid forms. Intially, commercially available inexpensive N-acetylglucosamine (GlcNAc) was converted to its N'-glycosyl p-toluenesulfonohydrazide in one step. Followed by chemical glycosylation, GlcNAcßProN3 was synthesized using this protecting group-free method in high yield (82%). Sequential one-pot multienzyme (OPME) ß1-3-galactosylation of GlcNAcßProN3 followed by OPME α1-4-fucosylation reactions produced target LeaßProN3 in gram-scale. Structurally diverse sialic acid forms was successfully introduced using a OPME sialylation reation containing a CMP-sialic acid synthetase and Pasteurella multocida α2-3-sialyltransferase 1 (PmST1) mutant PmST1 M144D with or without a sialic acid aldolase to form sLeaßProN3 containing naturally occurring or non-natural sialic acid forms in preparative scales.

Aqueous semisynthesis of C-glycoside glycamines from agarose.

Agarose was herein employed as starting material to produce primary, secondary and tertiary C-glycoside glycamines, including mono- and disaccharide structures. The semisynthetic approach utilized was generally based on polysaccharide-controlled hydrolysis followed by reductive amination. All reactions were conducted in aqueous media and without the need of hydroxyl group protection. We were able to identify optimal conditions for the reductive amination of agar hydrolysis products and to overcome the major difficulties related to this kind of reaction, also extending it to reducing anhydrosugars. The excess of ammonium acetate, methyl- or dimethylamine, and the use of a diluted basic (pH 11) reaction media were identified as important aspects to achieve improved yields, as well as to decrease the amount of byproducts commonly related to reductive amination of carbohydrates. This strategy allowed the transposition of the 3,6-anhydro-α-L-galactopyranose unit (naturally present in the agarose structure) to all glycamines synthesized, constituting an amino-substituted C-threofuranoside moiety, which is closely related to (+)-muscarine.

An α2,3-Linked Sialylglycopolymer as a Multivalent Glycoligand Against Avian and Human Influenza Viruses.

A glycopolymer bearing α2,3-linked sialyltrisaccharides was synthesized by living radical polymerization using a glycomonomer prepared by a protecting-group-free process, direct azidation of the free sialyllactose, and subsequent azide-alkyne cycloaddition. The prepared glycopolymer with pendant 3´-sialyllactose moieties strongly interacted with both avian and human influenza viruses analyzed by the hemagglutination inhibition assay and the quartz crystal microbalance method.

One-pot synthesis of enantiomerically pure N-protected allylic amines from N-protected α-amino esters.

An improved protocol for the synthesis of enantiomerically pure allylic amines is reported. N-Protected α-amino esters derived from natural amino acids were submitted to a one-pot tandem reduction-olefination process. The sequential reduction with DIBAL-H at -78 °C and subsequent in situ addition of organophosphorus reagents yielded the corresponding allylic amines without the need to isolate the intermediate aldehyde. This circumvents the problem of instability of the aldehydes. The method tolerates well both Wittig and Horner-Wadsworth-Emmons organophosphorus reagents. A better Z-(dia)stereoselectivity was observed when compared to the previous one-pot method. The (dia)stereoselectivity of the process was affected neither by the reaction solvent nor by the amount of DIBAL-H employed. The method is compatible with the presence of free hydroxy groups as shown with serine and threonine derivatives.