Search

A cascade double aryne insertion reaction was developed to generate a library of diarylmethane scaffolds. Additionally, chromone products were observed in presence of an electronegative atom at the ortho position of aryne.

An efficient and metal-free strategy for the synthesis of spiro-fused indanolactones/lactams has been developed for the reaction of arynes with α-chloroacetyl lactones/lactams. This strategy provides access to spiroindanone derivatives via aryne insertion/spirocyclization.

PDF file 136K,Methods: Additional information on experimental techniques and data analysis. Legends: describing supplementary figures S1-S14

PDF file 34156K, Table of genes from 16 recurrent amplified genomic regions (Figure S1), amplicon focality on TCGA copy number aberrations (Figure S2), hierarchical clustering of CLCGP copy number data (Figure S3), centrality frequencies of common cancer genes (Figure S4), genotypic cell line annotation (Figure S5), receptor signaling activation of H520 and HCC15 lines (Figure S6), experimental draft for ligand dependency (Figure S7), whole transcriptome analysis FGFR1 splicing (Figure S8), validation of gene expression by qPCR (Figure S9), tumor formation of FGFR1α cells in nude mice (Figure S10), quantification of MYC stains in murine tumor samples (Figure S11), apoptosis is accompanied by cytochrome c release and breakdown of mitochondrial potential (Figure S12), IHC scores of FGFR phosphorylation and MYC expression (Figure S13), High MYC expression identifies a second responder to FGFR inhibitory therapy (Figure S14)

A variety of aryne reactions are demonstrated in poly(ethylene glycol) dimethyl ethers (PEGDMEs) as solvents without the need of any additive. The reactions proceed efficiently and good yields of the desired products are observed with PEGDME. Further, the advantage of being able to recycle PEG solvents is demonstrated in this work.

Cyclic and acyclic vinyl substituted β-keto/enol carbonyl substrates, on reaction with arynes, result in differentially substituted naphthyl carbocycles, hitherto difficult to synthesize with existing protocols. While the substitutions on the arynes have no role, the ring size of the cyclic β-keto/enol esters has a profound influence on the product formation.

A scalable synthesis of l-allo-enduracididine is achieved from commercially available (S)-glycidol in ten linear steps involving well-established synthetic transformations. The synthetic route is flexible and can be used to synthesize all four diastereomers by changing the stereochemistry of glycidol and Sharpless asymmetric dihydroxylation reagent.

We report the efficient synthesis of cycloalkyl-fused naphthalenes through the [4 + 2]-cycloaddtion/decarboxylative aromatization of alkyne-tethered aryne insertion adducts. These scaffolds were difficult to synthesize using conventional reactions. The reaction proceeds via the formation of a benzopyrylium intermediate followed by intramolecular [4 + 2] cycloaddition and a subsequent decarboxylation pathway. This method is also compatible with allene-tethered substrates to afford similar products. In addition, the one-pot synthesis of polysubstituted naphthalenes via aryne insertion/benzannulation has also been developed in good yield.

A formal synthesis of (±)-cochlearol A was accomplished. The synthesis features Suzuki coupling and Friedel-Crafts cyclization as a convergent strategy to the functionalized tetralone ring and an intramolecular construction of the C/D ring involving sequential epoxide formation/acetal formation.

A domino approach to bridged cycloocta[b]indolone through a cascade of aza-Piancatelli rearrangement/Friedel-Crafts alkylation is developed. This transformation has been realized by reaction of an indole-tethered 2-furylcarbinol and substituted aniline in the presence of a Lewis acid to initiate aza-Piancatelli rearrangement followed by an in situ intramolecular Friedel-Crafts alkylation to access bridged tetracyclic frameworks in one pot.

A serendipitous synthesis of N-substituted 2-amino-2'-hydroxy-1,1'-biaryls through an aryne annulation with indolyl β-ketonitrile/ester in a cascade manner is demonstrated. The reaction sequence involves benzyne-mediated [2 + 2] Stoltz-type cycloaddition-cleavage and intramolecular Michael addition followed by C-N bond cleavage under transition-metal-free reaction conditions. Interestingly, while [4 + 2] Diels-Alder reaction is a possible pathway, no traces of the regioisomer was isolated.

This Essay highlights the complex issue of twinning in science publications. Historical accounts present cases where two scientists focused on the same problem and came up with the same solution following different paths. This has changed in the present day. The concurrent publication of rather similar research papers from different groups has increased in frequency since 2010. In the past, twinning in research publications was serendipitous, and there was a healthy competition among teams working on similar projects. Today, twinning has become more frequent. This can be attributed to the urge of researchers to have publications on popular topics, the tendency to base research programs on popular keywords, and funding agencies preferentially supporting certain areas of research. With vast amounts of literature being generated, editorial offices and referees may not be able to find these twins very easily. As we inch away from human ingenuity towards artificial intelligence, twinning may become even more frequent.

Drug discovery has brought new molecules for providing better cure for diseases. The process of discovering a new drug from the laboratory to market takes 12–15 years. Industries and academic insti...

A practical chemo-enzymatic process has been developed for the preparation of optically pure (S)-7-((tert-butyldiphenylsilyl)oxy)hept-1-yn-4-ol, (S)-4. This was prepared via enantioselective acylat...

Late-stage functionalization (LSF) aids drug discovery efforts by introducing functional groups onto C-H bonds on pre-existing skeletons. We adopted the LSF strategy to synthesize analogues of the abundantly available triterpenoid, glycyrrhetinic acid (GA), by introducing aryl groups in the A-ring, expanding the A-ring and selectively activating one methyl group of the gem-dimethyl groups. Intriguingly, two compounds were found to preferentially accumulate in the mitochondrial compartment of MDA-MB-231 breast cancer cells, to cause depolarization of mitochondrial membrane potential and to induce antiproliferative and anti-invasive effects through enhanced mitochondrial superoxide production with parallel depletion of GSH levels. Furthermore, intraperitoneal administration of these two compounds, in comparison with GA, greatly regressed breast tumor growth and metastasis in a SCID mouse model bearing labeled MDA-MB-231 cells.

An efficient and highly diastereoselective synthesis of CF3-dihydrobenzofurans by the reaction of in situ-generated CF3-oQMs in the presence of a base with sulphur ylides is put forward. The generality of the present developed method was well studied with diverse substrates to access the corresponding products in excellent yields. The highly reactive CF3-oQM has been utilized first time for the annulation reaction.

An efficient Mn-catalyzed cascade azide radical addition/cyclization/oxygen insertion reaction of alkyne-tethered cyclohexadienones with TMSN3 under mild conditions is reported. This domino reaction presents good diastereoselectivity generating bicyclic azido alcohol scaffolds which can be transformed into useful building blocks in organic synthesis for medicinal chemistry.

We report herein a scalable synthesis of linear heptapeptide side chain of the depsipeptide natural product teixobactin through solution phase. The synthesis of heptapeptide was achieved through an efficient coupling of suitably protected tripeptide and tetrapeptide comprising of three d-amino acids and four usual l-amino acid subunits.

The improved process for the synthesis of (±)-tapentadol, the FDA-approved analgesic drug, is achieved from tetrahydrothiopyran-4-one as the five-carbon source.

A domino approach to bridged cycloocta[

An efficient and highly diastereoselective synthesis of CF

Late-stage functionalization (LSF) aids drug discovery efforts by introducing functional groups onto C-H bonds on pre-existing skeletons. We adopted the LSF strategy to synthesize analogues of the abundantly available triterpenoid, glycyrrhetinic acid (GA), by introducing aryl groups in the A-ring, expanding the A-ring and selectively activating one methyl group of the gem-dimethyl groups. Intriguingly, two compounds were found to preferentially accumulate in the mitochondrial compartment of MDA-MB-231 breast cancer cells, to cause depolarization of mitochondrial membrane potential and to induce antiproliferative and anti-invasive effects through enhanced mitochondrial superoxide production with parallel depletion of GSH levels. Furthermore, intraperitoneal administration of these two compounds, in comparison with GA, greatly regressed breast tumor growth and metastasis in a SCID mouse model bearing labeled MDA-MB-231 cells.

A chiral-template-driven intramolecular Diels-Alder reaction has been used to build the tricyclic core of kalihinols, a group of antimalarial marine natural products. The key starting materials are commercially available nerol and sulcatone.

An efficient Mn-catalyzed cascade azide radical addition/cyclization/oxygen insertion reaction of alkyne-tethered cyclohexadienones with TMSN3 under mild conditions is reported. This domino reaction presents good diastereoselectivity generating bicyclic azido alcohol scaffolds which can be transformed into useful building blocks in organic synthesis for medicinal chemistry.

Graphical abstract, Remdesivir, the first drug approved by the FDA to treat COVID-19, is in high demand for patients infected with the SARS-CoV-2 virus. Herein, we report a facile approach minimizing the protecting group manipulations to afford remdesivir in good overall yield.

Benzyne insertion to build the privileged scaffold of a [6.8.6]-tricyclic framework on polycyclic and sp3-rich natural products has been developed. The formation of the [6.8.6]-tricyclic ring system is solvent dependent.

The FDA-approved drug for the treatment of asthma, zafirlukast, is synthesized engaging multiple catalytic reactions including a new method for the construction of 3-aroylindoles via oxidative cyclization. The highlights include transition-metal and peroxide free C–H bond activation using the stoichiometric amount of sodium persulfate as an oxidizing agent in the construction of 3-aroylindole, avoiding transition metal, with over 28% overall yield. The complete process has a turnaround time of 28 h to get the target molecule starting from substituted aniline, with practically no protecting groups.

The highly efficient and expedient route for the syntheses of 2-aroyl benzofurans has been developed via the cascade [2+2] followed by a [4+1] annulation on arynes. The overall transformation proceeded through the formation of ortho-quinone methide by the insertion of transient aryne into N, N-dimethylformamide and subsequent trapping with sulfur ylide. Moreover, this transformation has a broad range of substrate scope with a high functional-group tolerance. This new reaction was successfully utilized in the synthesis of the potent CYP19 aromatase inhibitor and late-stage functionalization on the bioactive complex estrone.

Stereoselective synthesis of northern fragment of eribulin mesylate is reported by coupling of the C1–C13 fragment with the C28–C35 fragment. The key steps involved in this synthesis are butyllithium-facilitated coupling between sulfone and aldehyde, then Dess–Martin periodinane oxidation followed by samarium(II) iodide mediated desulfonylation.

A pTSA catalyzed domino aza-Piancatelli rearrangement/Michael reaction was developed for the construction of 1,4-benzodiazepin-5-ones in one pot. The methodological studies offer broad scope and proceed well with various furfuryl carbinols as well as o-aminobenzamides giving medicinally relevant new chemical entities.

The total carbon framework with all chiral carbons of proposed structure of baulamycin A is synthesized using Evans’ aldol and Grubbs’ cross-metathesis as key reactions. This strategy enables one to access all the isomers of this natural product.

Total syntheses of three different lamellarins have been accomplished using a Ru(II)-catalyzed (3 + 2) annulation strategy to construct the central pyrrole ring. The striking features of this synthesis are the use of PEG-400 as a green solvent for the (3 + 2) annulation reaction and multiple catalytic reactions with excellent overall yield. The present route also enables the synthesis of various lamellarin analogues devoid of a B ring.

A metal free DBU catalyzed synthesis of 1,2,3-triazole-fused dihydrobenzoxazinone derivatives by tandem β-azidation/[3 + 2] cycloaddition reaction has been developed under mild conditions. The methodological studies offer a broad scope and proceed well with a wide range of alkynylated cyclohexa 2,5-dienones, giving new cis-triazole-fused tricyclic scaffolds.

Reasons to celebrate! The National Organic Symposium Trust (NOST) celebrated its 30th anniversary in 2018. This organization has been instrumental in shaping and influencing organic chemistry research in India.

Antituberculosis drugs have captured the attention of the scientific community due to the emergence of drug resistance. Hence, the development of new analogs and new drugs which can treat drug-resistant tuberculosis is required. In this report, we reviewed the strategies towards the synthesis of antituberculosis drugs. These strategies include semisynthetic approaches, resolution based strategies, microbial transformations, solid phase synthesis, and asymmetric synthesis. As stereochemistry is an important hallmark of many drugs, the strategies based on asymmetric synthesis are described in detail. The emphasis on semisynthetic approaches is given for aminoglycoside antibiotics.

The total synthesis of (±)-galanthamine is achieved in ∼5% overall yield using a key regioselective aryne insertion reaction into a GABA (γ-amino butyric acid) derivative. The strategy presented involves only two sub-critical temperature reactions and less than five chromatographic purifications to achieve the synthesis of galanthamine.

The ruthenium(II)-catalyzed hydration of terminal alkynes in PEG-400 to yield methyl ketones through Markovnikov addition of water across alkyne is reported.

Short and scalable synthesis of the complex pentacyclic indolosesquiterpene natural product mycoleptodiscin A has been achieved from commercially available diterpenoid (+)-sclareolide in 19% overall yield. This approach allows one to prepare various analogues of mycoleptodiscin using McMurry cyclization as a key reaction with just three chromatographic purifications.

The organocatalytic Diels–Alder reaction in non-conventional solvent (PEG-400) has yielded cycloaddition products with diastereoselectivities hitherto not reported in detail using classical reaction conditions.

(±)-Asenapine, sold in the market as Saphris/Sycrest for the treatment of bipolar disorders, is synthesized in an optically pure form involving an Ireland–Claisen rearrangement as the key step. This approach allows access to all diastereomers.

A series of thirteen 5 H -dibenzo [ b,e ][1,4]diazepin-11(10 H )-one structural derivatives has been synthesized and evaluated for anti-proliferative activity against five human cancer cell lines. Compound 9a exhibited potent tumour growth inhibition in all cell lines with IC 50 values in the range of 0.71–7.29 μM. Experiments on lung (A549) and breast (MDAMB-231) cancer cell lines to investigate the mechanisms of growth inhibition and apoptosis inducing effects of 9a showed that it arrested both cancer cell lines in the G2/M phase of cell cycle in a dose dependent manner. Hoechst staining analysis revealed that 9a inhibited tumour cell proliferation through apoptosis induction. Additionally, the mitochondrial membrane potential (ΔΨm) was affected and the levels of reactive oxygen species (ROS) were raised. The simple synthetic preparation and their biological properties make these dibenzodiazepinone-triazole scaffolds promising new entities for the development of cancer therapeutics.