Deciphering substitution effects on reductive hydroalkoxylation of alkynyl aminols for stereoselective synthesis of morpholines and 1,4-oxazepanes: total synthesis of tridemorph and fenpropimorph.

Acid catalysed reductive etherification of N-propargyl amino alcohols for the stereoselective synthesis of cis-2,5/2,6-disubstituted morpholines and cis-2,6/2,7-disubstituted oxazepanes has been developed. Mechanistic studies revealed that terminal alkynols gave morpholines via a 6-exo-dig hydroalkoxylation-isomerization-reduction cascade. Interestingly, an alkyne hydration-cyclization-reduction sequence is found to be involved in the formation of oxazepanes from alkyl substituted internal alkynols. The strategy was used as a key step in the total synthesis of fungicides tridemorph and fenpropimorph.

Iron-Mediated Hydrogen Atom Transfer Radical Cyclization of Alkenyl Indoles and Pyrroles Gives Their Fused Derivatives: Total Synthesis of Bruceolline E and H.

The iron-mediated hydrogen atom transfer (HAT) reaction is efficaciously employed for the synthesis of dihydropyrroloindoles and dihydropyrrolizines via 5-exo-trig radical cyclization where indoles and pyrroles are used as an acceptor. This radical approach has also been extended for the synthesis of tetrahydrocyclopenta[b]indolones via the Baldwin-disfavored 5-endo-trig cyclization pathway. The formal synthesis of bruceolline J and the total synthesis of bruceollines E and H have been expeditiously carried out by employing the former strategy.

Cascade radical cyclization on 3-propargyl-2-alkenyl indole gives stereoselective access to cyclohepta[b]indole over carbazole.

A protecting group-dependent diastereoselective synthesis of cyclohepta[b]indole over carbazole derivatives is developed. This strategy involves a regioselective 6-exo-trig radical cyclization-cyclopropanation-ring expansion cascade of 3-propargyl-2-alkenyl indole. The cascade radical cyclization was also performed on indole derivatives possessing alkyne, acrylate and vinylogous carbamate moieties, which delivered pyridocarbazole giving credence to the mechanistic hypothesis. Furthermore, cyclohepta[b]indole could be selectively converted to sulfone and sulfoxide as well as benzoazulenoindole via intramolecular Friedel-Crafts acylation.

Total Synthesis of Pyrrolidine and Piperidine Natural Products via TMSOTf-Mediated "5/6-endo-dig" Reductive Hydroamination of Enynyl Amines.

Stereoselective syntheses of pyrrolidines and piperidines bearing hydrophobic chains have been achieved through a metal free, Lewis acid-mediated 5/6-endo-dig reductive hydroamination cascade of enynyl amines. The brevity of the developed strategy allowed for the collective stereoselective total synthesis of various alkaloids, including (±)-pyrrolidine cis-225H, (±)-epi-197B, (±)-epi-225C, the family of (+)-solenopsins and (+)-isosolenopsins, and the formal synthesis of (±)-bgugaine and (+)-azimic acid.

Stereoselective Synthesis of Pyrrolo/Pyrido[2,1-a]isoindoles via Alkyne Iminium Ion Cyclization of Vinylogous Carbamates.

An efficient, acid-mediated, intramolecular alkyne iminium ion cyclization of oxoisoindolidene for the diastereoselective synthesis of pyrrolo/pyridoisoindole is described. This protocol features broad substrate scope and easy scalability. An unusual N to C-1,3-alkyl shift is observed with substrates bearing strong electron donating group at the phenyl ring attached to alkyne with concomitant hydration of alkyne to the ketone.

Hydroalkoxylation-Initiated Cascade on Sulfone-Tethered Aryl Alkynols Gives Cyclic and Spiro-Heterocyclic ß-Ketosulfones.

Serendipitous formation of cyclic ß-ketosulfones is observed when sulfone-tethered arylalkynols are reacted with base. The reaction involves a base-promoted propargyl sulfone to the allene isomerization/intramolecular hydroalkoxylation/retro-oxa-Michael/6-endo-trig Michael addition cascade. Sulfone-tethered alkynyl acrylates gave stereoselective access to a diverse array of spirocyclic ß-ketosulfone benzofuran/isochroman/indolines and sulfone-tethered bridged bicyclo[3.3.1]nonane. These cyclic ß-ketosulfones could be readily elaborated into benzofuran-fused cyclic sulfones and tetracyclic spiroindoline.

Cu(II)/PTABS-Promoted, Regioselective SNAr Amination of Polychlorinated Pyrimidines with Mechanistic Understanding.

Regioselective amination of polyhalogenated heteroarenes (especially pyrimidines) has extensive synthetic and commercial relevance for drug synthesis applications but is plagued by the lack of effective synthetic strategies. Herein, we report the Cu(II)/PTABS-promoted highly regioselective nucleophilic aromatic substitution (SNAr) of polychlorinated pyrimidines assisted by DFT predictions of the bond dissociation energies of different C-Cl bonds. The unique reactivity of Cu(II)-PTABS has been attributed to the coordination/activation mechanism that has been known to operate in these reactions, but further insights into the catalytic species have also been provided.

Lewis-Acid-Catalyzed Reductive Hydroalkoxylation of Propargylic N-Hydroxylamines Gives Stereoselective Access to Isoxazolidines.

Lewis-acid-catalyzed 5-endo-dig reductive hydroalkoxylation cascade on propargylic N-hydroxylamine gave expedient, stereoselective access to isoxazolidine derivatives. The developed method provides a new approach toward the synthesis of isoxazolidine, a biologically privileged scaffold. The synthetic potential of the developed methodology was demonstrated by synthesizing 1,3-aminoalcohol, 4-aminotetrahydropyran, and sedamine natural products.

Leveraging Alkyne-Oximium Cyclization for the Stereoselective Synthesis of Isoxazolidine.

A TMSOTf-mediated highly diastereoselective synthesis of isoxazolidine bearing three contiguous stereocenters is described. This method utilizes O-propargyl hydroxylamines as a novel building block for the rapid assembly of the isoxazolidines via alkyne-oximium cyclization. The strategy could be used in the synthesis of enantiomerically enriched isoxazolidines. Reductive cleavage of the N-O bond efficiently gives the corresponding 1,3-aminodiols with precise control over all stereocenters formed.

Heteroatom-Assisted Regio- and Stereoselective Palladium-Catalyzed Carboxylation of 9-Allyl Adenine.

Strategy for the synthesis of acyclic nucleoside analogs of biological relevance via highly regio- and stereoselective C-H functionalization employing heteroatom-assisted palladium-catalyzed carboxylation of 9-allyl adenine is disclosed. Substrate scope with different carboxylic acids was performed giving decent to good yields of the desired products. The method also allowed for the synthesis of deuterated analogs.

Transposition of an acrylate moiety in TMSOTf-mediated reaction of alkynyl vinylogous carbonates gives heterocyclic dienes.

TMSOTf-mediated reaction of alkynyl vinylogous carbonates serendipitously gave 1,4-oxazepine and dihydropyran dienes via transposition of an ethyl acrylate moiety involving intramolecular cascade Prins-type cyclization/retro-oxa-Michael reaction/cycloisomerisation. The developed atom-economical protocol selectively provides an E double bond geometry. Dihydropyran dienes could be reduced diastereoselectively using Et3SiH/TMSOTf or could be transformed into polycyclic heterocycles by Heck reaction.

Protecting Group-Dependent Synthesis of Densely Substituted Dihydropyrroles v/s Pyrroles via 5-Exo-trig Cascade Radical Cyclization to Alkynyl Vinylogous Carbamates.

Densely substituted dihydropyrroles could be synthesized with excellent diastereoselectivity via 5-exo-trig cascade radical cyclization to alkynyl vinylogous carbamates. N-Alkyl/acyl protected alkynyl vinylogous carbamates upon radical cyclization using thiophenol gave substituted pyrroles as against dihydropyrroles, which were formed with N-sulfonyl protecting groups. This enabled a rare example wherein both dihydropyrrole and pyrrole rings are assembled in the same reaction. This strategy could be used for the synthesis of an unprecedented adjacent polyheterocyclic system having a furan-thiophene-pyrrole motif. When vinylogous carbamate is embedded in the isoindole moiety, a pyridoisoindole derivative was formed with excellent diastereoselectivity, instead of the expected pyrroloisoindole product.

Recent Advances in Small Molecule-Based Intracellular pH Probes.

Intracellular pH plays an important role in many biological and pathological processes. Small-molecule based pH probes are found to be the most effective for pH sensing because of ease of preparation, high sensitivity, and quick response. They have many advantages such as small perturbation to the functions of the target, functional adaptability, cellular component-specific localization, etc. The present review highlights the flurry of recent activity in the development of such probes. The probes are categorized based on the type of fluorophore used like quinoline, coumarin, BODIPY, rhodamine, indolium, naphthalimide, etc., and their analytical performance is discussed.

Room temperature HFIP/Ag-promoted palladium-catalyzed C-H functionalization of benzothiazole with iodoarenes.

A versatile synthetic protocol involving the room temperature direct arylation of benzothiazole with a wide variety of iodoarenes under Ag-promoted Pd-catalyzed conditions in HFIP as the reaction solvent has been presented. A sequential HFIP-promoted selective iodination of arenes followed by Pd-catalyzed direct arylation of benzothiazole has also been disclosed. The utility of the developed protocol has been demonstrated by the synthesis of anti-tumor agents, PMX-610 and CJM-126 (precursor).

TMSOTf-Mediated Formal [4 + 2] Cycloaddition-Retro-aza-Michael Cascade of Vinylogous Carbamates for the Synthesis of Highly Fluorescent Pyridocarbazoles.

Trimethylsilyl trifluoromethanesulfonate mediated dimerization reaction of vinylogous carbamates of carbazoles gave highly fluorescent pyridocarbazoles through a Povarov-type formal [4 + 2] cycloaddition-retro-aza-Michael cascade. The developed strategy was used to access indolo pyridocarbazole and quinolizinocarbazolone in an expeditious manner. Various coupling reactions were successfully performed on synthesized pyridocarbazoles to study the effect of electronics of substitution on photophysical properties. Synthesized carbazoles possess excellent photophysical properties with high quantum yields (ΦF). Fluorescent carbazole dicarboxylic acid showed potential as a pH probe to give a linear response to pH over a very wide range (7.0-3.0) reflecting high efficiency.

Acid-catalysed iterative generation of o-quinone methides for the synthesis of dioxabicyclo[3.3.1]nonanes: total synthesis of myristicyclins A-B.

We report a practical and efficient method for the synthesis of bioactive flavanoids relying on the strategic use of o-quinine methide (o-QM) intermediates. This involves Brønsted acid-catalysed iterative generation of o-QMs/[4+2] cycloaddition/intermolecular Michael addition/cyclative acetalization in a cascade sequence for the synthesis of dioxabicyclo[3.3.1]nonanes. The 'one-pot', controlled cascade sequence successfully provided the shortest route amenable for gram scale synthesis of natural products (±)-myristicyclins A-B.

Recent advances in the synthesis of pyrrolo[1,2-a]indoles and their derivatives.

The pyrrolo[1,2-a]indole unit is a privileged heterocycle found in numerous natural products and has been shown to exhibit diverse pharmacological properties. Thus, recent years have witnessed immense interest from the synthesis community on the synthesis of this scaffold. In light of the ever-increasing demand for pyrrolo[1,2-a]indoles in drug discovery, this review provides an overview of recent synthesis methods for the preparation of pyrrolo[1,2-a]indoles and their derivatives. The mechanistic pathway and stereo-electronic factors affecting the yield and selectivity of the product are briefly explained. Furthermore, we have attempted to demonstrate the utility of the developed methods in the synthesis of bioactive molecules and natural products, wherever offered.

Design and Expeditious Synthesis of Quinoline-Pyrene-Based Ratiometric Fluorescent Probes for Targeting Lysosomal pH.

Intracellular pH plays a significant role in many pathological and physiological processes. A series of quinoline-pyrene probes were synthesized in one-step fashion through an oxonium-ion-triggered alkyne carboamination sequence involving C-C, C-O and C-N bond formation for intracellular pH sensing. The quinoline-pyrenes showed significant red shifts at low pH. Fluorescence lifetime decay measurements of the probes showed decreases in lifetime at pH 4. The probes showed excellent selectivity in the presence of various potential interfering agents such as amino acids and cations/anions. Furthermore, the probes were found to show completely reversible emission behaviour in the window between pH 4 and 7. A morpholine-substituted quinoline-pyrene probe efficiently stained lysosomes with high Pearson correlation coefficients (0.86) with Lysotracker Deep Red DND-99 as a reference. A co-localization study of the probe with Lysotracker DND-99 showed selective intracellular targeting and a shift in fluorescence emission due to acidic lysosomal pH.

Expeditious diastereoselective synthesis of medium ring heterocycle-fused chromenes via tandem 8/9-endo-dig and 8-exo-dig hydroalkoxylation-formal-[4 + 2] cycloaddition.

The first examples of highly diastereoselective tandem 8/9-endo-dig and 8-exo-dig hydroalkoxylation-formal-[4 + 2] cycloaddition are described for the synthesis of medium ring heterocycle-fused chromenes. TMS-alkynols preferred the exo-dig mode of hydroalkoxylation over the endo-dig mode leading to spiro-cyclic chromenes. The method could be used for the synthesis of linearly-fused ladder-like polyethers. A thia-heterocycle-fused chromene could be transformed into a complex bridged tricyclic ketal by a tandem carbene-insertion-[2,3]-sigmatropic shift.

TMSOTf mediated '5/6-endo-dig' reductive hydroamination for the stereoselective synthesis of pyrrolidine and piperidine derivatives.

A TMSOTf mediated 5/6-endo-dig reductive hydroamination cascade on internal alkynylamines gave expedient, stereoselective access to pyrrolidine and piperidine derivatives. We also demonstrate that a protecting group on nitrogen has a profound effect on the reactivity as well as diastereoselectivity of the reductive hydroamination cascade.