Divergent Synthesis of Organofluorinated Molecules from Titanium Mediated Deoxygenation of Free Alcohols

Comprehensive Summary Alcohols as among the most widely occurring organic compounds known,deoxygenative transformations of free alcohols as partners in radical addition reactions remain formidable challenges with great opportunities to achieve new and useful transformations.Herein,we report a protocol via C—O bond cleavage and C—C bond-forming reaction of trifluoromethyl alkenes with free alcohols assisted by titanium reagents via a deoxygenative radical strategy,enabling the divergent synthesis for functional-group-rich organofluorinated compounds in high efficiencies.In this transformation,tertiary alcohols by Ti-catalysis could be converted to trifluoromethyl alkanes without defluorination in acidic conditions,while benzyl alcohols are employed by Ti-mediated activation to supply the gem-difluoroalkenes with defluorination in the presence of a base.This protocol is applicable for a broad range of trifluoromethyl alkenes with good functional group tolerance and a variety of tertiary alcohols and benzyl alcohols(including primary。

Divergent synthesis of aryl amines and dihydroquinazolinones via electrochemistry-enabled rhodium-catalyzed C–H functionalization

Electrochemistry-enabled rhodium-catalyzed C–H amination and amination cyclization of arene assisted by a weakly coordinating amide have been reported. Additionally, aryl amines and dihydroquinazolinones could be obtained selectively by controlling the electric current. Mechanistic studies suggested that the amination reaction likely involves an electrochemical oxidation-induced reductive elimination of a high valent rhodium intermediate, which led to the amination reaction even proceeding smoothly at room temperature.

Transition-metal-switchable divergent synthesis of nitrile-containing pyrazolo[1,5-a]pyridines and indolizines

Palladium-catalyzed oxidative formal [4 + 1] annulation of pyridine-substituted acrylonitriles toward divergent fused N-heterocycles synthesis is reported. The heterodifunctionalization reaction with Cu(OAc);and urea as the nitrogen source accesses to nitrile-substituted pyrazolo[1,5-a]pyridines in moderate to good yields, while the homodifunctionalization reaction with FeBr;leads to synthesis of nitrilesubstituted indolizines in excellent yields.

Divergent Synthesis of Core m1,Core m2 and Core m3 O-Mannosyi Glycopeptides via a Chemoenzymatic Approach

O-Mannosylation plays a vital role in the regulation of a variety range of biological processes,for instance,brain and muscle development.However,the precise function remains largely unknown due to its innate heterogeneity.In this regard,it is still welcome to develop efficient methods to access diverse structurally-defined glycopeptides.In this study,a diversity-oriented assembly of O-mannosylα-dystroglycan(α-DG)glycopeptides has been achieved via a chemoenzymatic strategy.This strategy features(i)gram scale divergent synthesis of core m1,core m2 and core m3 mannosylated amino acids from judiciously designed protecting group strategies and chemical glycosidation;(i)efficient glycopeptide assembly via the optimized microwave-assisted solid phase peptide synthesis(SPpS);and(ii)enzymatic elaboration of the core glycan structures to install galactosyl and sialyl-galactosyl moieties.The efficiency and flexibility of this chemoenzymatic approach was demonstrated with the construction of 12 glycopeptides with different core m1,core m2 and core m3 mannosyl glycans,including a core m2 glycopeptide bearing a heptasaccharide for the first time.

A Divergent Synthesis of 1,8-Naphthyridines and Hydropyridopyrimidinones by the Reactions of o-Aminonitriles with Ketones

An efficient divergent synthesis of substituted 1,8-naphthyridine and hydropyridopyrimidinone derivatives was developed by the reactions of o-aminocyanopyridines and ketones based on different catalytic conditions.

Ni-catalyzed ligand-controlled divergent and selective synthesis

Scaffold diversity is a key feature of a compound library and plays a pivotal role in its success in biological screening.Therefore,it is highly desirable to develop efficient strategies to rapidly construct structurally distinct and diverse“privileged”molecular scaffolds,thereby giving rise to compound libraries with selective and differing biological activities.This review covers recent efforts in this emerging field of Ni-catalyzed divergent and selective synthesis,and will focus on reactions using the same substrate to generate structurally diverse molecular scaffolds by varying the ligand backbone under otherwise almost identical reaction conditions.We hope that the field will be encouraged by the progress achieved,drawing attention to the design and development of new selective catalytic systems,and revealing new modes of catalytic transformation for broader synthetic applications.

Recent advances of versatile reagents as controllable building blocks in organic synthesis

Diversity-oriented synthesis is a powerful and interesting synthetic tool for the rapid construction of structurally complex and privileged scaffolds from readily accessible starting materials.To date,diversity-oriented synthesis mostly relies on the employment of versatile reagents.Versatile reagents can be regulated as controllable and flexible building blocks for multipurpose utilizations.Over the past decade,a variety of multifunctional reagents have been developed.However,most versatile reagents usually need multi-step synthesis,thus restricting their wide application to a large extent.In terms of the practicalities and universalities,we prefer to pay more attention to the utilization of simple and practical versatile reagents with multiple reactivities,mainly including atropaldehyde acetals,aryl methyl ketones,vinylene carbonate,vinyl azides,aryldiazonium salts,rongalite,halodifluoromethyl compounds.Most importantly,these versatile reagents can also play different roles simultaneously in the same reaction,in which their different reactivities are converged into the final target products.Such strategy can not only offer more possibilities for the synthesis of several active pharmaceutical ingredients,but also minimize the occurrence of some side reactions by lessening the varieties of materials.Also,a perspective is given at the end of this review.

Total Synthesis of Stemarene and Betaerene Diterpenoids:Divergent Ring-Formation Strategy and Late-Stage C–H Functionalization

A unified protecting group-free approach to two stemarene and two betaerene diterpenoids through a bioinspired two-phase strategy has been developed,and three of them were obtained for the first time via chemical synthesis.Starting from a common intermediate,two distinct tetracyclic frameworks containing diastereoisomeric bridged bicycles were constructed by a divergent ring reorganization strategy.Late-stage C–H functionalization through a xanthylation-oxygenation protocol furnished the corresponding oxygenated stereocenters or oxo functionality in high regio-and diastereoselective fashion within a complex hydrocarbon system.The stereochemical puzzles in(–)-2-acetoxybetaer13(17)-ene and(+)-7-acetoxybetaer-13(17)-ene were first predicted by the comparison of density functional theory(DFT)-nuclear magnetic resonance(NMR)data with the reported data and then unambiguously addressed through the total syntheses of natural products and three diastereomers.

Synthesis of ester-capped carbosilane dendrimers via a hybrid divergent–convergent method

A series of novel ester-capped carbosilane dendrimers（G0-COOCH3–G2-COOCH3） were designed and successfully synthesized via a hybrid divergent–convergent method through a facile hydrosilylation reaction. The structures of these dendrimers were confirmed by FTIR,1H NMR, and HRMS analyses.

Photocatalytic divergent decarboxylative amination: a metal-free access to aliphatic amines and hydrazines

Nitrogen-containing motifs are widely present in natural products, bioactive molecules, and drugs. Accordingly, effective synthetic methods with high efficiency and diversity are highly desirable. Here, we present the invention of a facile, visible lightmediated decarboxylative C(sp^(3))–N bond-forming reaction by employing abundant carboxylic acids as the feedstock and a commercial diazirine as a nitrogen donor. This process is amenable to access both imines and diaziridines, as the corresponding masked amines and hydrazines, through a selectable single or double nitrogen transfer from the diazirine, respectively. This divergent approach works well in both directions with various alkyl carboxylic acids, including primary, secondary, and tertiary acids, as well as natural products and drugs, thus affording a rapid, metal-free approach to build nitrogen-containing molecule libraries with considerable structural diversity, which could thus benefit the related study in context of chemical biology and drug discovery.

Au(Ⅰ)-Catalyzed 6-endo-dig Cyclizations of Aromatic 1,5-Enynes to 2-(Naphthalen-2-yl)anilines Leading to Divergent Syntheses of Benzo[α]carbazole, Benzo[c,h]cinnoline and Dibenzo[i]phenanthridine Derivatives

A gold(Ⅰ)-catalyzed 6-endo-dig cyclization of aromatic 1,5-enynes was developed to synthesize 2-(naphthalen-2-yl)anilines.The functional group tolerance of this cyclization was examined systematically and a possible mechanism was proposed.The derivatization of 2-(naphthalen-2-yl)aniline was carried out to facile access to benzo[α]carbazole,benzo[c,h]cinnoline and dibenzo[i]phenanthridine derivatives in a divergent way.

Divergent pathways of β,γ-unsaturated α-diazocarbonyl compounds catalyzed by dirhodium and Lewis acids catalysts separately or in combination

β,γ-Unsaturated a-diazocarbonyl compounds possess two reactive sites for electrophilic addition-one at the diazo carbon and the other at the vinylogous γ-position.Controlled by catalyst,divergent transformations are achieved starting from the same starting materials,either by Lewis acid-catalyzed addition or by dirhodium-catalyzed metal carbene reactions.In select cases two catalysts working in combination or in sequence provide a relay for cascade transformations.In this review,we summarize advances in catalyst-dependent divergent transformations of β,γ-unsaturated α-diazocarbonyl compounds and highlight the potential of this exciting research area and the many challenges that remain.

Regiodivergent Access to 2- or 3-Substituted Indanones: Catalyst-Controlled Carboacylation via C–C Bond Activation

Indanones are ubiquitous in biologically active compounds.Intramolecular hydroacylation of aldehydes and alkenes is an efficient and atomeconomic route to indane rings.However,these reactions are limited to the transfer of a hydride to the alkene.The transfer of aryl groups enabling the formation of C–C bonds during the cyclization would be a new method for the synthesis of substituted indanones.This report describes the regiodivergent carboacylation of alkenes with ketones to furnish both 2-and 3-substituted indanones in a regiocontrolled manner.

Catalytic asymmetric Catellani-type reaction: A powerful tool for axial chirality construction

This highlight summarizes a recent development of a catalytic enantioselective Catellani-type reaction for the synthesis of axially chiral biaryls.The chirality induction is solely governed by chiral norbornene ligand in the Pd mediated ortho C–H functionalization and ipso cross-coupling transformation.The preparative power of the methodology is demonstrated as a powerful manifold for the divergent synthesis of structurally diverse axially chiral biaryls and chiral fluorenols.

Protecting-Group-Free One-Step Palladium-Catalyzed Coupling on C25 of Cucurbitacin B Expands Chemical Diversity with Improved Cytotoxicity against A549 Cells

The natural product cucurbitacin B has been widely studied because of its multiple biological activities,especially its potent antitumor effects.However,modifications of cucurbitacin B are mainly focused on the C2 and C16 site,studies on the C25 acetoxy group are still limited.We successfully developed a palladium-catalyzed allylic coupling of cucurbitacin B with boronic acids,providing a one-step approach to expand the chemical diversity of the C25 position.Our method was protecting-group-free,showing a good functional group tolerance and a wide substrate scope under mild reaction conditions.A library of 29 derivatives was prepared,compounds 2q and 2u showed higher cytotoxicity against A549 cells than cucurbitacin B,compounds 2n and 2o maintained potency,and the introduced hydroxyl and amino groups could be further derived.

Access to pyridines via cascade nucleophilic addition reaction of 1,2,3-triazines with activated ketones or acetonitriles

We studied the cascade nucleophilic addition reactions of 1,2,3-triazines with activated acetonitriles or ketones,which were used to construct highly substituted pyridines that are not easily accessed by conventional methods.The strategy addressed some structural diversity issues currently facing medicinal chemistry,and the resulting pyridines could be used as convenient precursors for the synthesis of related pharmaceuticals.In particular,our method was applied to the syntheses of the marketed drug etoricoxib and several biologically important molecules in a few steps.