Cu-Catalyzed Synthesis of Isoxazolidine/1,2-Oxazinane-3-ylidene Sulfonamide from O-Alkynyl Hydroxylamines: A Route to Sulfamethoxazole Analogues.

Cu-catalyzed cascade [3+2] azide-alkyne cycloaddition (CuAAC)/ketenimine/hydroamination reaction of alkynyl hydroxylamines that enables the rapid synthesis of isoxazolidine/1,2-oxazinane-3-ylidene sulfonamides. Notably, this study presents the first examples of 1,2-oxazinane-3-ylidene sulfonamide. The synthetic utility of this transformation is highlighted by the direct conversion of isoxazolidine-3-ylidine sulfonamides into 3-amino isoxazolines and isoxazole derivatives.

Lewis acid-promoted cascade reactions of cyclopropenes: a unified approach to stereoselective synthesis of cyclic ethers and oxaspirolactones.

Lewis acid-promoted 5/6- hydroalkoxylation/reduction cascade of ω-hydroxy cyclopropenes gave expeditious, stereoselective access to THF/THP derivatives. Monoester substituted ω-hydroxy cyclopropenes on treatment with catalytic Bi(OTf) lead to [5,5]/[6,5] oxaspirocyclic lactones. This unified strategy relies on generation of transient donor-acceptor (D-A) cyclopropanes from ω-hydroxy cyclopropene precursors.

Room temperature, metal-free, CDI-promoted, ex-situ protocol for S-methyl thioester synthesis.

S-methyl thioesters have proven to be useful intermediates in many biosynthetic reactions and their occurrence in bioactive molecules further enhance their appeal. Shortcomings in several reported synthetic protocols have led us to disclose herewith a mild, room temperature ex situ protocol that provides access to a large number of thioesters (aryl, heteroaryl, alkyl, amino acids). Late-stage functionalization strategies were also performed on commercial pharmaceutical drugs (containing carboxylic acid functionality) while further in situ conversion to valuable compounds has also been achieved.

MsOH Promoted Divergent Synthesis of 4-Arylidene Isoxazolidines and Isoxazolines from -Propargyl Hydroxylamines and Aldehydes.

Temperature-dependent, Brønsted-acid-mediated divergent synthesis of 4-arylidene isoxazolidines and isoxazolines from -propargyl hydroxylamines is developed. A series of control and crossover experiments have been carried out, revealing that the formation of 4-arylidene isoxazoline proceeds through an alkyne-oximium cyclization, ring-opening reaction, and subsequent condensation. Synthetic versatility of the developed methodology was highlighted in the synthesis of 3-aminoacrylaldehyde, β-hydroxy ketone, and isoxazole derivatives.

MHAT-enabled cascade radical annulation to access -fused indoles and pyrroles.

Iron-mediated hydrogen atom transfer (HAT) cascade annulation for the synthesis of -fused indole and pyrrole is disclosed. This robust cascade annulation assembles intricate heterocyclic motifs, such as tetrahydropyrido[1,2-]indoles and tetrahydroindolizines, equivalent to a formal [4+2] cycloaddition. The synthetic utility of the developed protocol was showcased in the synthesis of substituted tricyclic and tetracyclic heterocycles as well as an analogue of the natural product tashiromine.

BF·OEt Mediated Stereoselective Synthesis of 1,2-Heterocycle Fused Isoindolone Derivatives via Intramolecular Alkyne Oximium Cyclization of Oxoisoindolidene.

In this research we report Lewis acid mediated intramolecular alkyne oximium cyclization cascade on oxoisoindolidene for the stereoselective syntheses of isoxazolidine/oxazinane/oxazepane fused isoindolones bearing three chiral centers. The approach enables the construction of a new C-C and C-O bonds along with an aza-tertiary stereocenter. The developed protocol features a wide range of substrate scope, functional group tolerance, and has been utilized in the synthesis of tetracyclic lactone.

Alkynyl hydroxylamines: key precursors for 1,2-N/O heterocycles.

1,2-N/O Heterocycles are privileged scaffolds found in numerous natural products and have been shown to exhibit diverse pharmacological properties. Additionally, these compounds have emerged as important synthons in organic chemistry. Recent years have witnessed immense interest in these heterocycles from both the medicinal and the synthetic chemistry community.

Iron-Mediated Segment Coupling of Alkenols with Acceptors via C-C Radical Translocation and Remote Oxidative 1,5/6-Hydrogen Atom Transfer.

Iron-mediated segment coupling followed by oxidative 1,5/6-hydrogen atom transfer (HAT) for synthesis of ε-oxo alkene derivatives is developed. This transformation involved translocation of the radical from H-to-C-to-C-to-C followed by the oxidation under MHAT conditions providing rapid access to 1,6/1,7-keto functionalized esters/ketone/sulfones/phosphonates/arenes. The different outcomes of coupling with acceptors could be explained by bond dissociation energies (BDEs), and mechanistic insights were gained through control experiments, including deuterium labeling studies.

Iodine(III)-Mediated Keto-oximation of -Alkynyl Hydroxylamines: A Route to 3-Acyl Isoxazolines and 1,2-Oxazines.

An intramolecular iodine(III)-mediated keto-oximation of -alkynyl hydroxylamines offers rapid and straightforward access to 3-acyl Δ-isoxazolines and 1,2-oxazines. This approach features mild, metal-free, and aerobic reaction conditions with good functional group tolerance. Moreover, the synthetic utility of this method is demonstrated by the synthesis of unique structural motifs such as isoxazolidine, 3-vinyl isoxazoline, and 2,5-diphenylpyrazine derivatives by the conversion of 3-acyl Δ-isoxazolines, thereby showcasing its efficiency and applicability in synthetic chemistry.

Unlocking a reductive hydroalkoxylation cascade for the stereoselective synthesis of cyclic ethers: total synthesis of (±)-isolaurepan and (±)--lauthisan.

A Lewis acid-mediated, 5/6/7/8- reductive hydroalkoxylation cascade on enynols gives expeditious, diastereoselective access to small and medium ring cyclic ethers with a long aliphatic side chain. The brevity of the approach allowed a 4-step, stereoselective total synthesis of (±)-isolaurepan and (±)--lauthisan.

Harnessing Gold(I)-Catalyzed Hydroamination/1,3-Sulfonyl Migration Cascade for Divergent Synthesis of Isoxazolidine and Isoxazoline from -Alkynyl Hydroxylamine.

Gold-catalyzed 5- hydroamination on -homopropargylic hydroxylamine gave expeditious access to methylene isoxazolidine. Excess catalyst loading led to facile 1,3-sulfonyl migration in a cascade fashion to furnish the isoxazoline. Mechanistic studies using react-IR and NMR as well as crossover experiments indicated that 1,3-sulfonyl group migration is an intramolecular concerted process.

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 -propargyl amino alcohols for the stereoselective synthesis of -2,5/2,6-disubstituted morpholines and -2,6/2,7-disubstituted oxazepanes has been developed. Mechanistic studies revealed that terminal alkynols gave morpholines a 6- 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.

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-- radical cyclization where indoles and pyrroles are used as an acceptor. This radical approach has also been extended for the synthesis of tetrahydrocyclopenta[]indolones via the Baldwin-disfavored 5-- 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[]indole over carbazole.

A protecting group-dependent diastereoselective synthesis of cyclohepta[]indole over carbazole derivatives is developed. This strategy involves a regioselective 6- 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.

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 β-Ketosulfones.

Serendipitous formation of cyclic β-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--Michael/6-- Michael addition cascade. Sulfone-tethered alkynyl acrylates gave stereoselective access to a diverse array of spirocyclic β-ketosulfone benzofuran/isochroman/indolines and sulfone-tethered bridged bicyclo[3.

Total Synthesis of Pyrrolidine and Piperidine Natural Products via TMSOTf-Mediated "5/6-" 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- reductive hydroamination cascade of enynyl amines. The brevity of the developed strategy allowed for the collective stereoselective total synthesis of various alkaloids, including (±)-pyrrolidine -225H, (±)--197B, (±)--225C, the family of (+)-solenopsins and (+)-isosolenopsins, and the formal synthesis of (±)-bgugaine and (+)-azimic acid.

Cu(II)/PTABS-Promoted, Regioselective SAr 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 (SAr) 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 -Hydroxylamines Gives Stereoselective Access to Isoxazolidines.

Lewis-acid-catalyzed 5 reductive hydroalkoxylation cascade on propargylic -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 -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.

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 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 double bond geometry. Dihydropyran dienes could be reduced diastereoselectively using EtSiH/TMSOTf or could be transformed into polycyclic heterocycles by Heck reaction.

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

Densely substituted dihydropyrroles could be synthesized with excellent diastereoselectivity 5-- cascade radical cyclization to alkynyl vinylogous carbamates. -Alkyl/acyl protected alkynyl vinylogous carbamates upon radical cyclization using thiophenol gave substituted pyrroles as against dihydropyrroles, which were formed with -sulfonyl protecting groups. This enabled a rare example wherein both dihydropyrrole and pyrrole rings are assembled in the same reaction.

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).