Use Of Protecting Groups Research Articles

Cu-Catalyzed Amination of Base-Sensitive Aryl Bromides and the Chemoselective N- and O-Arylation of Amino Alcohols.

We report a general and functional-group-tolerant method for the Cu-catalyzed amination of base-sensitive aryl bromides including substrates possessing acidic functional groups and small five-membered heteroarenes. The results presented herein substantially expand the scope of Cu-catalyzed C-N coupling reactions. The combination of L8, an anionic N1,N2-diarylbenzene-1,2-diamine ligand, along with the mild base NaOTMS leads to the formation of a stable yet reactive catalyst that resists deactivation from coordination to heterocycles or charged intermediates. This system enables the use of low catalyst and ligand loadings. Exploiting the differences in nucleophile deprotonation in C-O and C-N coupling reactions catalyzed by Cu·L8 we developed a method to chemoselectively N- and O-arylate a variety of amino alcohol substrates. Employing NaOt-Bu as the base resulted exclusively in C-O coupling when the amino alcohols featured primary alcohols and more hindered amines or aniline groups. Utilizing NaOTMS enabled the ability to override the steric-based selectivity of these reactions completely and exclusively promoted C-N coupling regardless of the structure of the amino alcohol. The ability to invert the observed chemoselectivity is distinct from previously described methods that require protecting group manipulations or rely entirely on steric effects to control reactivity. These results substantially improve the scope of Cu-catalyzed C-N coupling reactions using N1,N2-diarylbenzene-1,2-diamine ligands and introduce a new chemoselective method to arylate amino alcohols.

Catalytic glycosylation for minimally protected donors and acceptors.

Oligosaccharides have myriad functions throughout biological processes1,2. Chemical synthesis of these structurally complex molecules facilitates investigation of their functions. With a dense concentration of stereocentres and hydroxyl groups, oligosaccharide assembly through O-glycosylation requires simultaneous control of site, stereo- and chemoselectivities3,4. Chemists have traditionally relied on protecting group manipulations for this purpose5-8, adding considerable synthetic work. Here we report a glycosylation platform that enables selective coupling between unprotected or minimally protected donor and acceptor sugars, producing 1,2-cis-O-glycosides in a catalyst-controlled, site-selective manner. Radical-based activation9 of allyl glycosyl sulfones forms glycosyl bromides. A designed aminoboronic acid catalyst brings this reactive intermediate close to an acceptor through a network of non-covalent hydrogen bonding and reversible covalent B-O bonding interactions, allowing precise glycosyl transfer. The site of glycosylation can be switched with different aminoboronic acid catalysts by affecting their interaction modes with substrates. The method accommodates a wide range of sugar types, amenable to the preparation of naturally occurring sugar chains and pentasaccharides containing 11 free hydroxyls. Experimental and computational studies provide insights into the origin of selectivity outcomes.

Integrated chemoenzymatic synthesis of a comprehensive sulfated ganglioside glycan library to decipher functional sulfoglycomics and sialoglycomics.

Ganglioside glycans are ubiquitous and complex biomolecules that are involved in a wide range of biological functions and disease processes. Variations in sialylation and sulfation render the structural complexity and diversity of ganglioside glycans, and influence protein-carbohydrate interactions. Structural and functional insights into the biological roles of these glycans are impeded due to the limited accessibility of well-defined structures. Here we report an integrated chemoenzymatic strategy for expeditious and systematic synthesis of a comprehensive 65-membered ganglioside glycan library covering all possible patterns of sulfation and sialylation. This strategy relies on the streamlined modular assembly of three common sialylated precursors by highly stereoselective iterative sialylation, modular site-specific sulfation through flexible orthogonal protecting-group manipulations and enzymatic-catalysed diversification using three sialyltransferase modules and a galactosidase module. These diverse ganglioside glycans enable exploration into their structure-function relationships using high-throughput glycan microarray technology, which reveals that different patterns of sulfation and sialylation on these glycans mediate their unique binding specificities.

HPLC-Based Automated Synthesis and Purification of Carbohydrates.

Reported herein is a new HPLC-based automated synthesizer (HPLC-A) capable of a temperature-controlled synthesis and purification of carbohydrates. The developed platform allows to perform various protecting group manipulations as well as the synthesis of O- and N-glycosides. A fully automated synthesis and purification was showcased in application to different carbohydrate derivatives including glycosides, oligosaccharides, glycopeptides, glycolipids, and nucleosides.

Scalable Total Synthesis of (+)-Desmethylxestospongin B.

Herein, the execution of synthetic strategies solving scalability issues observed in the original route is reported, increasing the total yield by 50% compared to the previously disclosed synthesis. A notable restructuring of the route's initial steps to reach a common allylic alcohol intermediate employs a highly stereoselective epoxidation method and avoids superfluous protecting group manipulations while limiting dependence on kinetic resolution in establishing stereochemistry for four of the six chiral centers in (+)-desmethylxestospongin B. Different protecting group strategies to avoid problems with their subsequent removal were considered and enacted; to this end, material was retained as byproducts were suppressed. While the lactam semireduction under Birch conditions requires further investigation, the updated synthesis of (+)-desmethylxestospongin B reported here made it more scalable, affording 0.37 g of this natural product for continued biological studies.

Donor Preactivation-Based Glycan Assembly: from Manual to Automated Synthesis.

Carbohydrates are called the third chain of life. Carbohydrates participate in many important biochemical functions in living species, and the biological information carried by them is several orders of magnitude larger than that of nucleic acids and proteins. However, due to the intrinsic complexity and heterogeneity of carbohydrate structures, furnishing pure and structurally well-defined glycans for functional studies is a formidable task, especially for homogeneous large-size glycans. To address this issue, we have developed a donor preactivation-based one-pot glycosylation strategy enabling multiple sequential glycosylations in a single reaction vessel.The donor preactivation-based one-pot glycosylation refers to the strategy in which the glycosyl donor is activated in the absence of a glycosyl acceptor to generate a reactive intermediate. Subsequently, the glycosyl acceptor with the same anomeric leaving group is added, leading to a glycosyl coupling reaction, which is then iterated to rapidly achieve the desired glycan in the same reactor. The advantages of this strategy include the following: (1) unique chemoselectivity is obtained after preactivation; (2) it is independent of the reactivity of glycosyl donors; (3) multiple-step glycosylations are enabled without the need for intermediate purification; (4) only stoichiometric building blocks are required without complex protecting group manipulations. Using this protocol, a range of glycans including tumor-associated carbohydrate antigens, various glycosaminoglycans, complex N-glycans, and diverse bacterial glycans have been synthesized manually. Gratifyingly, the synthesis of mycobacterial arabinogalactan containing 92 monosaccharide units has been achieved, which created a precedent in the field of polysaccharide synthesis. Recently, the synthesis of a highly branched arabinogalactan from traditional Chinese medicine featuring 140 monosaccharide units has been also accomplished to evaluate its anti-pancreatic-cancer activity. In the spirit of green and sustainable chemistry, this strategy can also be applied to light-driven glycosylation reactions, where either UV or visible light can be used for the activation of glycosyl donors.Automated synthesis is an advanced approach to the construction of complex glycans. Based on the two preactivation modes (general promoter activation mode and light-induced activation mode), a universal and highly efficient automated solution-phase synthesizer was further developed to drive glycan assembly from manual to automated synthesis. Using this synthesizer, a library of oligosaccharides covering various glycoforms and glycosidic linkages was assembled rapidly, either in a general promoter-activation mode or in a light-induced-activation mode. The automated synthesis of a fully protected fondaparinux pentasaccharide was realized on a gram scale. Furthermore, the automated synthesis of large-size polysaccharides was performed, allowing the assembly of arabinans up to an astonishing 1080-mer using the automated multiplicative synthesis strategy, taking glycan synthesis to a new height far beyond the synthesis of nucleic acids (up to 200-mer) and proteins (up to 472-mer).

Deprotective Functionalization: A Direct Conversion of Nms-Amides to Carboxamides Using Carboxylic Acids.

The nature of protecting group chemistry necessitates a deprotection step to restore the initially blocked functionality prior to further transformation. As this aspect of protecting group manipulation inevitably adds to the step count of any synthetic sequence, the development of methods enabling simultaneous deprotection and functionalization ("deprotective functionalization"-distinct from "deprotection followed by functionalization") is appealing, as it has the potential to improve efficiency and streamline synthetic routes. Herein, we report a deprotective functionalization of the newly introduced Nms-amides guided by density functional theory (DFT) analysis, which exploits the inherent Nms reactivity. Mechanistic studies further substantiate and help rationalize the exquisite reactivity of Nms-amides, as other commonly used protecting groups are shown not to exhibit the same reactivity patterns. The practicality of this approach was ultimately demonstrated in selected case studies.

Recent progress in chemoenzymatic synthesis of human glycans.

Glycan is an essential cell component that usually exists in either a free form or a glycoconjugated form. Glycosylation affects the regulatory function of glycoconjugates in health and disease development, indicating the key role of glycan in organisms. Because of the complexity and diversity of glycan structures, it is challenging to prepare structurally well-defined glycans, which hinders the investigation of biological functions at the molecular level. Chemoenzymatic synthesis is an attractive approach for preparing complex glycans, because it avoids tedious protecting group manipulations in chemical synthesis and ensures high regio- and stereo-selectivity of glucosides during glycan assembly. Herein, enzymes, such as glycosyltransferases (GTs) and glycosidases (GHs), and sugar donors involved in the chemoenzymatic synthesis of human glycans are initially discussed. Many state-of-the-art chemoenzymatic methodologies are subsequently displayed and summarized to illustrate the development of synthetic human glycans, for example, N- and O-linked glycans, human milk oligosaccharides, and glycosaminoglycans. Thus, we provide an overview of recent chemoenzymatic synthetic designs and applications for synthesizing complex human glycans, along with insights into the limitations and perspectives of the current methods.

Practical N-to-C peptide synthesis with minimal protecting groups

Accessible drug modalities have continued to increase in number in recent years. Peptides play a central role as pharmaceuticals and biomaterials in these new drug modalities. Although traditional peptide synthesis using chain-elongation from C- to N-terminus is reliable, it produces large quantities of chemical waste derived from protecting groups and condensation reagents, which place a heavy burden on the environment. Here we report an alternative N-to-C elongation strategy utilizing catalytic peptide thioacid formation and oxidative peptide bond formation with main chain-unprotected amino acids under aerobic conditions. This method is applicable to both iterative peptide couplings and convergent fragment couplings without requiring elaborate condensation reagents and protecting group manipulations. A recyclable N-hydroxy pyridone additive effectively suppresses epimerization at the elongating chain. We demonstrate the practicality of this method by showcasing a straightforward synthesis of the nonapeptide DSIP. This method further opens the door to clean and atom-efficient peptide synthesis.

Concise total synthesis of (±)-Dibromoagelaspongin

Marine alkaloids containing a diaminoimidazole-derived core possess intriguing chemical structures and have displayed promising antimicrobial activity in preliminary screens. However, the synthesis of these compounds has been hindered by a paucity of methods to generate the densely functionalized multicyclic cores, which contain relatively large numbers of nitrogen atoms. In this work, we report a novel total synthesis of the marine alkaloid (±)-dibromoagelaspongin. Our key intermediate is a 2,5-diaminoisoimidazole accessed in one step from a guanylhydrazine and an amidoketone through a [3,3]-sigmatropic rearrangement-elimination sequence. The incorporation of the densely functionalized core in a single step bypassed the need for redox and protecting group manipulations, and the natural product was obtained in fewer than half the number of steps of the sole prior published route in excellent overall yield.

Strategic application of C-H oxidation in natural product total synthesis.

The oxidation of unactivated C-H bonds has emerged as an effective tactic in natural product synthesis and has altered how chemists approach the synthesis of complex molecules. The use of C-H oxidation methods has simplified the process of synthesis planning by expanding the choice of starting materials, limiting functional group interconversion and protecting group manipulations, and enabling late-stage diversification. In this Review, we propose classifications for C-H oxidations on the basis of their strategic purpose: type 1, which installs functionality that is used to establish the carbon skeleton of the target; type 2, which is used to construct a heterocyclic ring; and type 3, which installs peripheral functional groups. The reactions are further divided based on whether they are directed or undirected. For each classification, examples from recent literature are analysed. Finally, we provide two case studies of syntheses from our laboratory that were streamlined by the judicious use of C-H oxidation reactions.

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.

Preparation of a 4'-Thiouridine Building-Block for Solid-Phase Oligonucleotide Synthesis.

Starting from a commercially available thioether, we report a nine-step synthesis of a 4'-thiouridine phosphoramidite building-block. We install the uracil nucleobase using Pummerer-type glycosylation of a sulfoxide intermediate followed by a series of protecting group manipulations to deliver the desired phosphite. Notably, we introduce a 3',5'-O-di-tert-butylsilylene protecting group within a 4'-thiosugar framework, harnessing this to ensure regiospecific installation of the 2'-O-silyl protecting group. We envisage this methodology will be generally applicable to other 4'-thionucleosides and duly support the exploration of their inclusion within related nucleic acid syntheses. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: (2R,3S,4R)-2,3-O-Isopopropylidene-5-O-tert-butyldiphenylsilyl-1-(4-sulfinyl)cyclopentane: Sulfoxidation Basic Protocol 2: 2',3'-O-Isopropylidene-5'-O-tert-butyldiphenylsilyl-4'-thiouridine: Pummerer glycosylation Basic Protocol 3: 4'-Thiouridine: Deprotection Basic Protocol 4: 2'-O-tert-Butyldimethylsilyl-3',5'-di-tert-butylsiloxy-4'-thiouridine: 2',3',5'-O-silylation Basic Protocol 5: 2'-O-tert-Butyldimethylsilyl-4'-thiouridine: Selective 3'-5'-desilylation Basic Protocol 6: 2'-O-tert-Butyldimethylsilyl-5'-O-dimethoxytrityl-4'-thiouridine: 5'-O-dimethoxytritylation Basic Protocol 7: 2'-O-tert-butyldimethylsilyl-3'-O-[(2-cyanoethoxy)(N,N-diisopropylamino)phosphino]-5'-O-dimethoxytrityl-4'-thiouridine: 3'-O-phosphitylation.

Investigations into the Aqueous Synthesis of Selenoglycoconjugates

AbstractGlycosylation of bioactive molecules has been found to improve the pharmacokinetic properties of the parent molecule. However, their syntheses often require tedious protecting group manipulations. The development of methodologies which allow direct aqueous conversion of unprotected sugars into glycosides is therefore an ambitious goal. Herein, we present a broadly applicable method for the synthesis of selenoglycosides in water. We show the ease of direct conjugation of unprotected glycosyl diselenides with various biomolecules, including resorcinol, resveratrol, and the antitumor agent, gimeracil, furnishing the corresponding selenoglycoconjugates in up to 96 % yield. We also demonstrate the oxidatively‐triggered release of the bioactive drug from the sugar, priming these molecules for medicinal applications. The generality and broad substrate scope of this novel transformation will provide access to various selenium‐containing glycomimetics and glycoconjugates.

Synthesis of Highly Functionalized Bismacycles via Post-Transmetallation Modification of Arylboronic Acids.

Bismacycles featuring a sulfone-bridged scaffold have recently been developed as versatile and convenient electrophilic arylating agents. Here, we report that the exocyclic aryl group, which is ultimately transferred to a nucleophilic coupling partner, can be functionalized through cross-coupling, heteroatom substitutions, oxidations and reductions, and protecting group manipulations. This "postsynthetic modification" approach provides concise and divergent access to complex aryl bismacycles. The utility of the functionalized bismacycles in electrophilic arylation of C-H and O-H bonds is demonstrated.

Total Synthesis of (+)-Aberrarone

The structurally intriguing diterpene (+)-aberrarone has been assembled in only 12 steps from the commercially available (S,S)-carveol without protecting group manipulations. This concise synthesis features a Cu-catalyzed asymmetric hydroboration to generate the chiral methyl group, a Ni-catalyzed reductive coupling to link two fragments, and a Mn-mediated radical cascade cyclization to construct the triquinane system.

β-1,2-Oligomannan phosphorylase-mediated synthesis of potential oligosaccharide vaccine candidates

β-(1,2)-Mannan antigens incorporated into vaccines candidates for immunization studies, showed that antibodies raised against β-(1,2)-mannotriose antigens can protect against disseminated candidiasis.Until recently, β-(1,2)- mannans could only be obtained by isolation from microbial cultures, or by lengthy synthetic strategies involving protecting group manipulation. The discovery of two β-(1,2)-mannoside phosphorylases, Teth514_1788 and Teth514_1789, allowed efficient access to these compounds. In this work, Teth514_1788 was utilised to generate β-(1,2)-mannan antigens, tri- and tetra-saccharides, decorated with a conjugation tether at the reducing end, suitable to be incorporated on a carrier en-route to novel vaccine candidates, illustrated here by conjugation of the trisaccharide to BSA.

Half-Sandwich Type Platinum-Group Metal Complexes of C-Glucosaminyl Azines: Synthesis and Antineoplastic and Antimicrobial Activities

While platinum-based compounds such as cisplatin form the backbone of chemotherapy, the use of these compounds is limited by resistance and toxicity, driving the development of novel complexes with cytostatic properties. In this study, we synthesized a set of half-sandwich complexes of platinum-group metal ions (Ru(II), Os(II), Ir(III) and Rh(III)) with an N,N-bidentate ligand comprising a C-glucosaminyl group and a heterocycle, such as pyridine, pyridazine, pyrimidine, pyrazine or quinoline. The sugar-containing ligands themselves are unknown compounds and were obtained by nucleophilic additions of lithiated heterocycles to O-perbenzylated 2-nitro-glucal. Reduction of the adducts and, where necessary, subsequent protecting group manipulations furnished the above C-glucosaminyl heterocycles in their O-perbenzylated, O-perbenzoylated and O-unprotected forms. The derived complexes were tested on A2780 ovarian cancer cells. Pyridine, pyrazine and pyridazine-containing complexes proved to be cytostatic and cytotoxic on A2780 cells, while pyrimidine and quinoline derivatives were inactive. The best complexes contained pyridine as the heterocycle. The metal ion with polyhapto arene/arenyl moiety also impacted on the biological activity of the complexes. Ruthenium complexes with p-cymene and iridium complexes with Cp* had the best performance in ovarian cancer cells, followed by osmium complexes with p-cymene and rhodium complexes with Cp*. Finally, the chemical nature of the protective groups on the hydroxyl groups of the carbohydrate moiety were also key determinants of bioactivity; in particular, O-benzyl groups were superior to O-benzoyl groups. The IC50 values of the complexes were in the low micromolar range, and, importantly, the complexes were less active against primary, untransformed human dermal fibroblasts; however, the anticipated therapeutic window is narrow. The bioactive complexes exerted cytostasis on a set of carcinomas such as cell models of glioblastoma, as well as breast and pancreatic cancers. Furthermore, the same complexes exhibited bacteriostatic properties against multiresistant Gram-positive Staphylococcus aureus and Enterococcus clinical isolates in the low micromolar range.

Synthesis of a Bifunctionalized Glycosylphosphatidylinositol (GPI) Anchor Useful for the Study of GPI Biology.

A new, bifunctional glycosylphosphatidylinositol (GPI) derivative containing the highly conserved core structure of all natural GPI anchors with a photoactivable diazirine in the lipid chain and clickable alkynes in the glycan was synthesized by a convergent [3+2] glycosylation strategy with late stage protecting group manipulation and regioselective phosphorylation. The challenges of this synthesis were due to the presence of several distinctive functional groups in the synthetic target, which complicated the protection tactics, in addition to the inherent difficulties associated with GPI synthesis. This bifunctional GPI derivative can cross-react with molecules in proximity upon photoactivation and be subsequently labeled with other molecular tags via click reaction. Therefore, it should be a valuable probe for biological studies of GPIs, such as analysis of GPI-interacting membrane proteins, and gaining insights into their functional mechanisms.

Synthesis of Adagrasib (MRTX849), a Covalent KRASG12C Inhibitor Drug for the Treatment of Cancer

A concise, transition-metal and protection-free synthesis of adagrasib (MRTX849), a novel KRASG12C inhibitor drug recently approved by the FDA, is reported. Introduction of two chiral building blocks to the tetrahydropyridopyrimidine core was accomplished via two sequential SNAr reactions. Extensive reaction optimization led to a robust, transition-metal-free oxidation of the sulfide intermediate. A judicious choice of the leaving group with favorable steric and electronic characteristics at the 4-OH position of the tetrahydropyridopyrimidine core enabled a facile SNAr displacement to introduce the chiral piperazine. This new, five-step, chromatography-free synthesis of adagrasib from readily available starting materials obviated the palladium catalysis and protecting group manipulations in the current commercial route and significantly improved the efficiency of the process in 45% overall yield.