A full account of our total synthesis of aleutianamine (1) is disclosed. An initial α-thioketone derivatization approach was thwarted by a failed enolate functionalization. A second-generation approach employing palladium-catalyzed Barbier addition enabled the successful construction of the [3.3.1]bicyclononane moiety of the natural product, but unsuccessful downstream functionalization and poor material throughput led to the abandonment of this approach. Along the way, a one-pot Larock indolization/Buchwald-Hartwig amination cascade was developed for the synthesis of tricyclic diaminoindole derivatives. Eventually, the total synthesis was accomplished via a novel dearomative arylation of an aminothiophene, which allowed rapid access to the molecular skeleton of aleutianamine including the challenging bridgehead sulfide. Following construction of the core, cerium-mediated oxidative amination and palladium-catalyzed decarboxylative pinacol-type rearrangement enabled chemoselective introduction of the C10 aniline and alkenyl bromide, leading to the total synthesis of aleutianamine.
Mushrooms are a rich source of steroidal compounds and have attracted attention from scientists for long. Recently, we found that several naturally occurring steroidal compounds including chaxine B (1) could be generated non-enzymatically from ergosterol, a major component of the fungal cell membrane. Here, we conducted further analyses to determine that the reactions require radical intermediates by using the radical trap TEMPO but proceed without light or heat. Steric hindrance led to the formation of only a limited number of adducts. We then conducted computational analyses of the reaction pathways to propose and evaluate the mechanisms of non-enzymatic formation of the ergosterol derivatives having unusual and diverse ring systems. The analyses revealed the occurrence of a common intermediate Int-4, from which 1 and its diastereomer BB (2), as well as newly identified pleurocin-type compound 5, could be formed. The calculated activation energies of the reaction pathways from Int-4 to the precursors of 1 and 2 were low enough to proceed at 25 °C, and the identified precursors indeed transformed spontaneously to 1 and 2 in aqueous solutions. These results highlight the difficulty and complexity of biosynthetic studies of ergosterol derivatives, where the reactions could proceed either enzymatically or non-enzymatically.
Robust methods to access 3,3-disubstituted oxetanes are desired due to the attractive physicochemical properties offered by the polar 4-membered rings and their potential use as replacement groups for carbonyl or gem-dimethyl functionality in medicinal chemistry. The generation of benzylic oxetane carbocations from oxetanols offers considerable potential, particularly in the generation of diaryloxetanes, a structural type that is seldom reported. To date, however, Friedel-Crafts reactions have been limited to oxetanols bearing an electron-rich aromatic group due to the carbocation destabilizing nature of the oxetane. Here, an alternative Fe-catalyzed Friedel-Crafts reaction is described, employing HFIP as a solvent, enabling oxetanyl carbocation formation directly from oxetanols bearing phenyl and other electron-poor arenes. HFIP with its strong hydrogen bond donor (HBD) ability and enhanced Brønsted acidity cooperatively promotes the generation of the carbocations in the presence of the Lewis acid. The oxetane-HFIP adduct was detected, likely formed reversibly as a stabilizing off-cycle intermediate. The developed methodology enabled the concise synthesis of oxetane analogues of Fenofibrate and Tesmilifene, replacing diarylmethane and benzophenone motifs, respectively. Additional mechanistic studies into the fate of these carbocation intermediates provide insights into the reaction mechanism.
In this paper, a density functional theory (DFT) study to characterize the reaction mechanism and the origin of stereoselectivity of the NHC-catalyzed reaction of 1-cyclopropylcarbaldehyde and α-alkynyl enal has been presented. Both the cyclopropylcarbaldehyde-first and α-alkynyl enal-first mechanisms were examined. The calculation results show that the cyclopropylcarbaldehyde-first mechanism is more favorable than the α-alkynyl enal-first mechanism. The nucleophilic addition to α-alkynyl enal is the stereochemistry-determining step that preferentially affords the RR-dihydropyranone. The calculated results correlate well with the experimental findings. The origins of regio- and enantioselectivities were investigated using Parr function, distortion-interaction, noncovalent interaction (NCI), and atoms in molecules (AIM) analyses. The observed stereoselectivity can be attributed to differential distortion and interactions in the nucleophilic addition transition states. The effects of substituents and solvents were also explored and discussed. This study will be helpful for understanding the reaction mechanism and guiding the future design of highly selective catalytic reactions.
This study provides insight into the donor characteristics of the indole framework and allows a comparison between its C-2 and C-3 positions. Ten electron-rich alkynes incorporating an indole core were synthesized via the Sonogashira cross-coupling reaction. Structural variations within these substrates led to two distinct reaction pathways for the formation of cyano-containing conjugated systems, yielding eight tricyanovinylation and two [2 + 2] cycloaddition-retroelectrocyclization (CA-RE) products. The tricyanovinylation products formed with tetracyanoethylene (TCNE) were obtained in 40-82% yields, whereas the chromophores produced through the [2 + 2] CA-RE pathway arising from alkyne activation were isolated in 30-63% yields. They display pronounced intramolecular charge transfer (ICT), with λmax values ranging from 494 to 504 nm for the tricyanovinylation products, while the two [2 + 2] CA-RE chromophores absorb at 471 and 495 nm. The observed ICT bands are supported by UV/vis studies by positive solvatochromism and protonation experiments. To clarify the relationship between NLO response and ICT properties, the dipole moment, band gap, electronegativity, average global hardness-softness, average polarizability, and first hyperpolarizability parameters were evaluated using computational methods. In addition to theoretical DFT calculations, the EFISHG technique was employed to investigate the NLO properties. The experimental μβ values of the selected molecules range from 150 to 560 × 10-48 esu.
The development of nitrogen- and sulfur-containing heterocycles remains a central challenge in modern synthetic chemistry owing to their structural diversity and biological relevance. Herein, we report the synthesis of the ionic liquid (IL) 1-dodecyl-1-methylpiperidinium chloride ([C12mpip][Cl]) and, for the first time, its application as an efficient catalyst in an unprecedented divergent one-pot cyclization. The protocol enables the cyclization of 6-aminobenzothiazole with diverse aryl or heteroaryl aldehydes and 1,3-dimethylbarbituric acid in ethanol as a green solvent under reflux conditions. Apart from ortho-substituted and NH-unsubstituted heteroaryl aldehydes, the reaction proceeds with high regio- and diastereoselectivity to afford spiro[pyrimidine-5,8'-thiazolo[5,4-f]quinoline]triones 4(a-l) in yields of up to 94% and diastereomeric ratios exceeding >99:1 (syn:anti). Notably, the reaction outcome is governed by the aldehyde substitution pattern, enabling controlled access to structurally distinct fused heterocycles under identical conditions. The method constructs two new stereogenic centers and multiple σ-bonds in a single operation and is readily scalable to the gram scale with consistently high yields. All structures were confirmed by spectroscopic techniques and single-crystal X-ray analysis. Antiproliferative evaluation across six solid tumor cell lines identified compound 4l as a lead candidate, displaying uniform single-digit micromolar GI50 values (1.22-7.40 μM) and potent activity against patient-derived glioblastoma (GBM6) cells (GI50 = 2.40 μM). Compound 5b also exhibited consistent low-micromolar growth inhibition across multiple cancer cell lines. The operational simplicity, scalability, and promising biological profile facilitated gram-scale synthesis with yields of up to 94%.
The oxidation of 3-amino-1H-indazole was reported independently by Hünig and Pozharskii approximately 50 years ago and proposed to yield an azo compound via a Baeyer-Mills-type mechanism. However, the structural assignment lacked complete evidence, leaving the identity of the obtained product uncertain. To unambiguously determine the correct structure, the oxidation under basic conditions was reinvestigated, revealing two distinct products depending on the loading of t-BuLi. The obtained compounds were systematically characterized by 1D/2D NMR techniques and X-ray diffraction, leading to the conclusion that the Hünig's "deep-red" compound corresponds to the structure assigned as (E)-1-[(3H-indazo-3-ylidene)amino]-1H-3-amine, whereas Pozharskii's "orange" compound is indeed an azoazole, featuring an E-configuration in the azo bond rather than the Z-configuration reported in 1977. This investigation resolves discrepancies among previous literature reports regarding the oxidation of 3-amino-1H-indazole and unifies them within a single coherent framework.
Embedding π-conjugated units into peptide backbones enables control over π-π interactions and promotes energy transfer within fibrillar nanostructures resembling those formed from natural β-sheet-rich proteins. As a result, peptide sequences that naturally form or favor β-sheet architectures are commonly used in the construction of these systems. Most amino acid residues generally promote the formation of β-sheet structures; however, proline is usually viewed as a β-blocker that favors more helical structures. Consequently, our previous π-peptide studies excluded proline-containing sequences. In this study, we investigate how the incorporation of proline into π-peptides identified computationally for its ability to foster strong intermolecular electronic coupling affects the electronic and structural behavior of the resulting π -conjugated peptide nanostructures. Despite the expectation that proline would disrupt β-sheet organization, simulations and cryo-EM studies suggest that curved conformations of the π-peptide can still foster the formation of hydrogen-bonding and π-stacked assemblies. Using UV-vis, PL, and CD spectroscopies, we explore how proline's structure and stereochemistry (D/L form) influence the photophysical properties and supramolecular chirality of these assemblies.
Herein, we developed a novel protocol for the visible-light-catalyzed synthesis of multifunctional pyrrole-2-ones from N-arylglycines (1) and cyclopropenones (2) through decarboxylation, radical addition, and ring expansion reactions. Furthermore, this cascade reaction requires only 0.08 equivalents of 4CzIPN to facilitate the photocatalytic decarboxylation, free radical addition, and ring expansion reactions, thereby eliminating the need for any transition metal catalyst. Target compounds 3a-3l' were obtained in moderate to excellent yields (57%-96%) by employing 4CzIPN as the photocatalyst, NaHCO3 as the base, and propylene carbonate (PC) as the green solvent under an argon atmosphere with blue light irradiation for 3 h. The reaction does not require any metal catalyst or heating, has a wide substrate scope, is environmentally friendly and sustainable, boasts a high atom economy, and exhibits significant regioselectivity. This strategy facilitated the synthesis of pyrrole-2-ones bearing quaternary centers with potential biological activity, expanding the applications of N-arylglycine as a C2 synthon in the construction of pyrrole-2-one frameworks via room-temperature photochemical reactions.
The excited-state dynamics and photochemical behavior of mono-, di-, and trisubstituted triphenylamines were investigated in different media by nanosecond laser flash photolysis. Photoexcitation produces the triplet excited state of the triarylamines, which undergoes competitive radiationless decay and intramolecular [6π]-electrocyclization to form the corresponding triplet N-aryl-4a,4b-dihydrocarbazoles. These intermediates subsequently yield singlet dihydrocarbazoles that undergo back-electrocyclization, disproportionation, or oxygen trapping. The transient species were characterized by their absorption spectra, lifetimes, quantum yields, and kinetic parameters. Both the efficiency of electrocyclization and the rate of radiationless deactivation depend strongly on solvent polarity and substituent electronic effects. Linear correlations between rate constants and Reichardt's solvent polarity parameter point out that cyclization is favored in polar solvents, whereas radiationless decay predominates in nonpolar media. Hammett analyses further demonstrate systematic substituent effects on the competing excited-state pathways, including triarylamines bearing perfluoroalkyl substituents. These results provide a comprehensive kinetic and mechanistic description of the photoinduced electrocyclization of substituted triphenylamines and establish quantitative relationships between molecular structure, solvent environment, and excited-state reactivity.
Four polyhydroxylated dihydro-oxazines have been synthesized as competitive products of well-known nitrones from corresponding carbohydrates through efficient and practical procedures involving a five-to-seven-steps sequence in moderate overall yields (15%-35%). The key SN2 N- or O-attack ring-cyclization steps to afford the desired dihydro-oxazines were found to be significantly influenced by fluoride concentration, alkalinity, and water content in the reaction system. Reactivities of d- and l-ribose-derived polyhydroxylated dihydro-oxazines were then fully screened under reduction and nucleophilic organometallic addition conditions, revealing them as excellent synthons in affording versatile products including C-1 modified N,O-ketal, 1,2-oxazinanes, and related nitrile derivatives under different conditions. Subsequently, a compound library containing 34 polyhydroxylated 1,2-oxazinanes was established and subjected to thorough glycosidase inhibition and an anticancer study. While most of them showed no inhibition of the tested glycosidases, part of these compounds demonstrated moderate or weak inhibitory activities against the MOLT-4 cell line, providing implications for subsequent screening of related iminosugar derivatives with potential anticancer activities.
A practical, robust, and straightforward access to optically enriched allylamines by a regio- and diastereoselective 1,2-addition of organolithium reagents to Davis-Ellman-type chiral conjugated sulfinimines is reported. The procedure is operationally simple, proceeds under mild conditions, requires readily available starting materials, and consistently delivers complete regiocontrol in favor of 1,2-addition. Synthetically useful levels of diastereoselectivity can be obtained in all cases, and the reaction tolerates a broad range of organolithium reagents and substitution patterns on the sulfinimine. The method further enables a one-pot 1,2-addition/N-functionalization sequence through in situ trapping of the transient lithiated sulfinamide, constituting a formal 1,2-difunctionalization of the C═N bond and expanding the structural diversity accessible in a single operation.
Metal hydride intermediates play a central role in transition-metal catalysis, yet the intrinsic reactivity modes and selectivity-governing features of cationic Ir-H species remain poorly understood. Herein, a comprehensive density functional theory (DFT) study is reported to elucidate the mechanism and stereochemical origins of an Ir(I)-catalyzed asymmetric hydroalkylation of alkenes. The calculations reveal that the active cationic Ir-H intermediate preferentially undergoes a concerted β-H elimination rather than charge-separated H-transfer pathways, despite the inherent polarity of the Ir-H bond. Subsequent alkene difunctionalization proceeds through a sequence of migratory insertion steps, among which the Ir-C/C═O migratory insertion is identified as both the rate-determining and stereochemistry-determining step. Distortion/interaction-activation strain analyses show that unfavorable interaction energies associated with polarized Ir-H/C═O insertion disfavor competing pathways, while sterically guided Ir-C/C═O insertion is kinetically preferred. Detailed transition-state analyses and steric contour maps demonstrate that the Ir-H-centered chiral environment acts as an active steric regulator, governing both enantio- and diastereoselectivity. These findings provide a unified mechanistic framework for Ir-H-mediated hydrofunctionalization reactions and highlight the critical role of cationic Ir-H species in controlling reactivity and selectivity.
The preparation and reactivity of a series of ortho-halogen-substituted (diacetoxyiodo)arenes, [hydroxy(tosyloxy)iodo]arenes, and aryliodonium ylides are reported. X-ray analysis of 1-[hydroxy(tosyloxy)iodo]-2-bromobenzene confirms the presence of halogen bonds in the intramolecular interactions between the ortho-halogen atom and the hypervalent iodine center, with a normalized contact (observed contact length divided by the sum of the van der Waals radii) value of 0.91. The o-bromo-substituted aryliodonium ylide can be handled and stored at room temperature and can serve as a convenient carbene precursor in a Rh-catalyzed cyclopropanation reaction with styrenes, affording the corresponding cyclopropane products in 59-75% yields.
Both cinnoline and furanone are the pivotal skeletons of numerous natural products and pharmaceuticals. While a number of reliable methods for the respective synthesis of cinnoline or furanone derivatives are currently available, concurrent construction of these two privileged scaffolds in one pot has not been disclosed. We report herein a concise and convenient synthesis of cinnoline fused furanone from the easily obtainable and economically sustainable phenylhydrazine and maleimide. Mechanistically, the formation of product involves C-H bond activation-initiated cinnoline ring forming along with the maleimide ring opening, followed by an intramolecular O-nucleophilic addition to form the furanone skeleton. Notably, this tandem annulation process is realized via C-H/C-N/C-N bond activation and C-C/C-N/C-O bond formation featuring an interesting formal oxygen swap. This novel reaction not only enriches the chemical space of phenylhydrazine and maleimide as versatile synthetic building blocks, but also provides a reliable approach toward the biologically promising fused N/O heterocycles with advantages such as simple substrates, good efficiency, free of external oxidant, high atom-economy and ready scalability.
A chiral-pool-based divergent strategy enables asymmetric synthesis of iridoid monoterpenoids (+)-isoboonein, (-)-boschnialactone, (+)-scholarein A (putative structure), and the (+)-dioxa-[5.5.5.6] fenestrane core of asperaculin A. Our synthesis features a stereoselective intramolecular Pauson-Khand reaction (IPKR) on a chiral enyne ether as the pivotal step, along with other stereoselective synthetic manipulations. Strategic extension of a readily accessible enediyne ether-based chiral precursor further facilitated one-pot tandem IPKR-anchored, tidy access to the tetracyclic fenestrane core of asperaculin A.
We describe the synthesis, photophysical properties, and ab initio calculations on a series of 2-(2'-hydroxyphenyl)benzazoles (HBX), functionalized by a benzonitrile, prone to boost the fluorescent quantum yield in solution. HBX are well known to display the excited-state intramolecular proton transfer (ESIPT) process, but they typically lead to a quenched fluorescence in solution. The additional insertion of an ethynyl-triisopropylsilane substituent in the vicinity of the benzonitrile group acts as a cooperative moiety to obtain strong multiple-state emissive transitions with distinct emission wavelengths. Quantum yields of the ESIPT transition are up to 52% in solution, which are among the record values in the literature. The photophysical data can be further modulated by the nature of the heteroatom constitutive of HBX, paving the way for the development of ultrasensitive ratiometric probes.
Aryl C-glycosides are an important class of carbohydrate derivatives known for their exceptional stability and significant biological relevance; however, C-2 aryl glycosides remain rare and synthetically challenging targets. Herein, we report a mild and efficient palladium-catalyzed protocol for the stereoselective synthesis of 2-aryl-4-ketoglycosides from protected and unprotected 2,3-d-pseudoglycals using aryl diazonium salts. The transformation proceeds smoothly at room temperature under ligand and base-free conditions, affording the desired products in good to excellent yields with high stereocontrol. The methodology exhibits a broad substrate scope, tolerating aryl diazonium salts bearing electron-donating, electron-withdrawing, and halogen substituents, as well as a variety of benzyl-, alkyl-, silyl-protected and unprotected pseudoglycals. Notably, halogen substituents are retained, enabling further downstream functionalization. The protocol is also applicable to unprotected 2,3-pseudorhamnal and can be extended to a one-pot process from anilines via in situ diazonium formation. Gram-scale synthesis and postfunctionalization highlight the robustness and synthetic utility of the method. Overall, this operationally simple and practical strategy provides a general and stereoselective route to C-2 aryl glycosides, expanding access to valuable carbohydrate scaffolds for applications in medicinal chemistry and chemical biology.
We introduce a divergent and straightforward synthetic approach for the synthesis of quinoxaline and α-ketothioamide derivatives from easily accessible Bunte salts under mild reaction conditions. The transformation proceeds through an unusual and sequential C-S bond cleavage followed by subsequent S-S bond scission. I2-mediated conditions enable the synthesis of quinoxalines with 1,2-diamines, while elemental sulfur promotes the synthesis of α-ketothioamides using primary and secondary amines. The protocol proceeds at room temperature under mild conditions, delivers products in good to excellent yields, and demonstrates broad functional group compatibility and scalability.
Herein, we report a novel visible-light-mediated electron donor-acceptor (EDA) complex-promoted three-component perfluoroalkylation/cyclization strategy. Enaminones, perfluoroalkanes, and anilines underwent direct cyclization in the presence of DABCO under visible-light irradiation, efficiently constructing perfluoroalkyl-substituted quinoline derivatives. The key innovation of this transformation lies in the utilization of an EDA complex formed between perfluoroalkanes and an organic base to drive the reaction, delivering the target products in good to excellent yields. This protocol provides a new pathway for the efficient construction of perfluoroalkyl-substituted quinoline scaffolds, which holds significant potential in medicinal chemistry and materials science.