Intramolecular Nitrone Interrupted Click Reaction.

We document the intramolecular interception of a Cu-catalyzed azidoalkyne cycloaddition employing a suitably placed nitrone group, providing a simple route to the unprecedented spiro-polyheterocyclic scaffold. The reaction is comprised of a Cu-catalyzed [3 + 2]-cycloaddition of (2-azidoaryl)isatogen with a terminal alkyne and the intramolecular trapping of the transient Cu-triazolide intermediate with the isatogen, with a net formation of one C-C and two C-N bonds and the new heterocyclic ring being spiro-annulated.

Synthesis, characterization, and crystal structure of 2-(2-azido-phen-yl)-3-oxo-3H-indole 1-oxide.

An attempt to explore the reactivity of the nitro group in the presence of gold catalysis in comparison to the azide group yielded intriguing results. Surprisingly, only the nitro group exhibited reactivity, ultimately giving rise to the formation of the title isatogen, C14H8N4O2. In the crystal structure, weak C-H⋯O hydrogen bonds and π-π stacking inter-actions link the mol-ecules. The structure exhibits disorder of the mol-ecule.

Construction of the quinobenzoxazine core via gold-catalyzed dual annulation of azide-tethered alkynones with anthranils.

A new catalytic method for the construction of the quinobenzoxazine core has been developed employing the gold-catalyzed cyclization of o-azidoacetylenic ketones in the presence of anthranils. The overall process comprises of a gold-catalyzed 6-endo-dig cyclisation of o-azidoacetylenic ketone leading to a α-imino gold carbene and subsequent carbene transfer to anthranil leading to the 3-aryl-imino-quinoline-4-one intermediate, which undergoes 6π-electrocyclization and aromatization to form the central quinobenzoxazine core. This transformation provides a new approach to a diverse array of quinobenzoxazine structures, in addition to being scalable and having mild reaction conditions.

Postmodification of voxelotor (GBT 440) via [Rh]-catalyzed cross dehydrogenative coupling with olefins.

The directed Rh(III)-catalyzed cross dehydrogenative coupling of the pyrazole unit of the GBT-440 scaffold has been explored with simple as well as conjugated olefins to synthesize post-functionalized GBT-440 analogues. The screening of these synthesized compounds for improving the oxygen binding efficiency of the hemoglobin isolated from the sickled red blood cells revealed that some of these compounds are as good as GBT-440.

Facile synthesis of the spiro-pyridoindolone scaffold via a gold-catalysed intramolecular alkynol cyclisation/hydroindolylation.

A simple approach for the synthesis of pyridoindolone scaffolds with a spiroannulated tetrahydrofuran ring is described. The overall process comprises intramolecular sequential gold-catalysed 5-endo-dig alkynol cycloisomerization and subsequent addition of indole C2 to the in situ generated oxocarbenium cation.

Rediscovering Bacon's hydrazine/phenylhydrazine mediated cyclization of 2,2'-dicarbonylbi(hetero)aryls: construction of (5-azo)-/indazolo[2,3-a]quinolines.

Hydrazine/phenylhydrazine-mediated reductive dicarbonyl coupling reactions have been carried out under mild conditions to provide polycyclic aromatic compounds and azo-substituted polyaromatic compounds. This method has a broad substrate scope with good functional group compatibility.

Total synthesis of the pseudoindoxyl class of natural products.

The pseudoindoxyl sub-structural motif, amongst the large set of the indole class of alkaloids, represents a unique subset of the oxygenated indole class of the alkaloid family. A majority of this class of natural products contains complex bridged/polycyclic scaffolds with interesting biological profiles. They are thus attractive synthetic targets. Starting from 1963, twenty-eight natural products having the pseudoindoxyl scaffold have been isolated, among which the synthesis of 13 natural products has been accomplished. In this review, we highlight the completed as well as the formal total synthesis of the natural products with a spiro-pseudoindoxyl ring, with a focus on their development. The challenges and the future perspective based on the recent developments in the field will also be discussed. We strongly believe that this review will not only update but also attract the attention of researchers in dealing with the synthesis of pseudoindoxyl compounds.

Gold-Catalyzed Complementary Nitroalkyne Internal Redox Process: A DFT Study.

Gold-catalysis, in this century, is one of the most emerging and promising new areas of research in organic synthesis. During the last two decades, a wide range of distinct synthetic methodologies have been unveiled employing homogeneous gold catalysis and aptly applied in the synthesis of numerous natural products and biologically active molecules. Among these, the reactions involving α-oxo gold carbene/α-imino gold carbene intermediates are of contemporary interest, in view of their synthetic potential and also due to the need to understand the bonding involved in these complexes. In this manuscript, we document the theoretical investigations on the regio-selectivity dependence of substitution on the gold-catalyzed cycloisomerization of o-nitroarylalkyne derivatives. We have also studied the relative stabilities of α-oxo gold carbene intermediates.

Intermolecular Interception of α-Oxo Gold Carbenes of Nitroalkyne Cycloisomerization with 1,2-Benzo[d]isoxazole: Synthesis of Functionalized Quinazoline 1-Oxides.

The known nitrogen-transfer reagent 1,2-benzo[d]isoxazole has been used to trap the postulated α-oxo gold carbene intermediate involved in the [Au]-catalyzed internal redox process of 2-alkynylnitrobenzenes. This process led us to develop a general convergent method for the synthesis of highly functionalized quinazoline 1-oxides.

Gold-Catalysed Nitroalkyne Cycloisomerization - Synthetic Utility.

The gold-catalysed intramolecular redox cyclization of o-alkynylnitrobenzens documented by Professors Naoki Asao and Yoshinori Yamamoto is an important discovery that has opened two complementary research domains. Advancing this cyclization with other metals as well as developing new methods around the products that result from this reaction is one aspect that has seen growing interest. On the other hand, the idea of generating α-oxo gold carbenes via oxygen transfer to alkynes has established another important aspect in gold-catalysis. In this account, we will be dealing with the first aspect, which revolves around the internal redox cyclization of nitroalkynes (trivially called as nitroalkyne cycloisomerization), focusing mainly on the gold-complexes and the synthetic methods developed around it from our group and from other groups, and also providing the details of similar transformations documented with other metals so that the complementary reactivity/diversity of these transformations could be appreciated.

A concise/catalytic approach for the construction of the C14-C28 fragment of eribulin.

A simple approach for the synthesis of the C14-C28 fragment of eribulin has been developed by employing a one-pot gold-catalyzed alkynol cyclization/Kishi reduction to construct the 1,5-cis-tetrahydropyran unit and a cross-metathesis/Sharpless asymmetric dihydroxylation-cycloetherification to install the 1,4-trans-tetrahydrofuran ring. Use of easily accessible building blocks, ease of operation and catalytic transformations as key reactions for the construction of THF/THP units highlight the current approach.

Interrupting the [Au]-Catalyzed Nitroalkyne Cycloisomerization: Trapping the Putative α-Oxo Gold Carbene with Benzo[c]isoxazole.

The [Au]-catalyzed nitroalkyne cycloisomerization of 2-alkynylnitrobenzenes leading to anthranils has been interrupted by possible trapping of the postulated intermediate α-oxo gold carbene with an external nucleophile such as benzo[c]isoxazole (anthranil). At the outset, this provides a simple synthesis of highly functionalized 3-acyl-(2-formylphenyl)-2H-indazoles with the sequential C-O, C-N, and N-N bond formations. This provides indirect support for the existence of α-oxo gold carbenes in the [Au]-catalyzed internal redox processes of nitroalkynes.

Oxidative Rearrangement of Stilbenes to 2,2-Diaryl-2-hydroxyacetaldehydes.

A one-pot oxone-mediated/iodine-catalyzed oxidative rearrangement of stilbenes leading to 2,2-diaryl-2-hydroxyacetaldehydes is described. Control experiments revealed that a 2,2-diarylacetaldehyde was initially formed that undergoes subsequent α-hydroxylation. The resulting α-hydroxyaldehydes have been subjected to a one-pot Still-Gennari olefination followed by cyclization, leading to 5,5-diaryl-γ-butenolides.

Total Synthesis of (+)-Petromyroxol, (-)-iso-Petromyroxol, and Possible Diastereomers.

The total synthesis of (+)-petromyroxol (1) and its seven diastereomers including the (-)-iso-petromyroxol (2) is described. The employed strategy involves the use of easily available C5-epimeric epoxides 5 and 5' and nonselective anomeric C1-allylation, proceeding with or without inversion at C2, thereby giving the possibility of synthesizing all possible diastereomers. Extensive two-dimensional (2D) NMR analyses of all eight diastereomers have been carried out to assign the chemical shifts of the central carbons and the corresponding attached hydrogens and to learn how the C/H-chemical shifts of the tetrahydrofuran ring were influenced by the adjacent centers.

An Apparent Umpolung Reactivity of Indole through [Au]-Catalysed Cyclisation and Lewis-Acid-Mediated Allylation.

The sequential functionalization of indole C2 and C3 in an umpolung fashion was executed with a predesigned substrate and choice of reagents. The developed method comprises gold-catalysed alkynol cycloisomerisation/intramolecular addition of C2 of indole and subsequent BF3 ⋅OEt2 -mediated regioselective C3 allylation, resulting in the synthesis of the functionalized indoloisoquinolinone scaffold. The reaction involves 5-endo-alkynol cycloisomerisation and the dearomative addition of indole C2 to the intermediate oxocarbenium cation, which results in two equilibrating fused and spiropentacyclic intermediates, which upon treatment with allyl silane in the presence of BF3 ⋅OEt2 , undergo selective indole C3 allylation. Other nucleophiles, such as hydride, azide and indole, were also found to be compatible with this process.

NADP-dependent glutamate dehydrogenases in a dimorphic zygomycete Benjaminiella poitrasii: Purification, characterization and their evaluation as an antifungal drug target.

BACKGROUND: It has been reported that the genes coding for NADP-dependent glutamate dehydrogenases (NADP-GDHs) showed a cause-effect relationship with Yeast-Hypha (YH) reversible transition in a zygomycete Benjaminiella poitrasii. As YH transition is significant in human pathogenic fungi for their survival and proliferation in the host, the NADP-GDHs can be explored as antifungal drug targets. METHODS: The yeast-form specific BpNADPGDH I and hyphal-form specific BpNADPGDH II of B. poitrasii were purified by heterologous expression in E. coli BL-21 cells and characterized. The structural analogs of L-glutamate, dimethyl esters of isophthalic acid (DMIP) and its derivatives were designed, synthesized and screened for inhibition of NADP-GDH activity as well as YH transition in B. poitrasii, and also in human pathogenic Candida albicans strains. RESULTS: The BpNADPGDH I and BpNADPGDH II were found to be homo-hexameric proteins with native molecular mass of 282 kDa and 298 kDa, respectively and subunit molecular weights of 47 kDa and 49 kDa, respectively. Besides the distinct kinetic properties, BpNADPGDH I and BpNADPGDH II were found to be regulated by cAMP-dependent- and Calmodulin (CaM) dependent- protein kinases, respectively. The DMIP compounds showed a more pronounced effect on H-form specific BpNADPGDH II and inhibited YH transition as well as growth in B. poitrasii and C. albicans strains. CONCLUSION: The present study will be useful to design and develop antifungal drugs against dimorphic human pathogens using glutamate dehydrogenase as a target. SIGNIFICANCE: Glutamate dehydrogenases can be explored as a target against human pathogenic fungi.

Discovery of 3-(benzofuran-2-ylmethyl)-1H-indole derivatives as potential autophagy inducers in cervical cancer cells.

In this manuscript we have documented the identification of a novel anticancer scaffold 3-(benzofuran-2-ylmethyl)-1H-indole. This scaffold has been designed by tweaking the known bisindolylmethane scaffold of natural products that display a wide range of biological activities. A series of 24 new conjugates have been synthesized and among them 5 derivatives exhibited IC50 values less than 40 µM against two cervical cancer cell lines SiHa and C33a. Further mechanistic studies of two compounds 3eb and 3ec revealed that the toxicity of these compounds was due to the effective induction of autophagy mediated cell death. The autophagy induction was confirmed by the progressive conversion of LC3I to LC3II and downregulation of p62 in cervical cancer cells.

Studies toward the Total Synthesis of Parvifolals A/B: An Intramolecular o-Quinone Methide [4 + 2]-Cycloaddition To Construct the Central Tetracyclic Core.

Two different approaches funded upon the intramolecular [4 + 2]-cycloaddition of in situ generated o-quinone methides have been explored to construct the central tetracyclic core of parvifolals A/B. At the outset, a cross-pinacol coupling of 2-formyl tri-O-methyl resveratrol with 4-methoxysalicylaldehyde followed by acid treatment was found to provide the desired tetracyclic core with an internal olefin. The requisite pendant aryl group has been introduced by a Pd-catalyzed direct coupling of corresponding diazonium salt.

One-Pot Au[III]-/Lewis Acid Catalyzed Cycloisomerization of Nitroalkynes and [3 + 3]Cycloaddition with Donor-Acceptor Cyclopropanes.

A one-pot protocol for the synthesis of a tricyclic pseudoindoxyl scaffold from 2-nitroalkynylbenzenes, comprising of an Au(III)-catalyzed nitroalkyne cycloisomerization leading to isatogen and its [3 + 3]-cycloaddition with donor-acceptor cyclopropanes mediated by a suitable Lewis acid, has been developed.

Ru(II)-Catalyzed C-H Activation/Alkylation of 3-Formylbenzofurans with Conjugated Olefins: Product Divergence.

Ru-catalyzed alkylation of 3-formylbenzofuran with acrylates and acrylamides has been described. Branched selectivity with unsubstituted or ß-substituted acrylates/acrylamides and linear selectivity with α-substituted acrylates have been observed. However, in all of the cases, the intermediate alkylation products seem to undergo further reactions, either cycloannulation or deformylation, depending on the substrate employed. For example, with methyl acrylate, the intermediate branched alkylation product underwent cycloannulation with another molecule of methyl acrylate, resulting in a densely functionalized cyclohexene ring formation. On the other hand, in the case of N-monosubstituted acrylamides, the branched alkylation proceeded with intramolecular aldehyde-amide condensation, leading to pyridin-2-one ring annulation. However, with both methacrylate and crotonate, deformylation of the initially formed alkylation products was observed.