Neuroplastogens, small molecules that induce beneficial neuronal growth and plasticity, are a class of compounds emerging as new drugs for treating a range of central nervous system conditions. Clausenamide is a plasticity-promoting natural product isolated from the leaves of Clausena lansium, an evergreen native to Southeast Asia and southern China. Herein, we report an efficient synthesis of this compound by a one-pot, three-component assembly of three of the four contiguous stereogenic centers. This method enabled efficient access to six stereoisomers and one analog, which were evaluated for their ability to induce synaptogenesis in primary cortical cultures using high-content imaging. We observed a range of activities for clausenamide stereoisomers, but in general, the postsynaptic effects of the active compounds were greater than their presynaptic effects. Of the stereoisomers tested, (-)-cis-clausenamide exhibited the highest level of cortical synaptogenesis, with this effect likely being dependent on its ability to act as a 5-HT2AR partial agonist.

Although cyclic SIAs have demonstrated promising medicinal potential, methodologies for their construction remain relatively scarce. SIAs have proven to be suitable nitrene precursors for aziridination and C-H amination, when mixed with hypervalent iodine and a metal catalyst. Herein, we report the intramolecular cyclization of SIAs featuring N-acyl-type substitution via a dirhodium nitrene intermediate, forming a new N-heteroatom bond. The reaction leads to a diverse array of aromatic heterocyclic products featuring stereogenic sulfur centers. A combination of computational and spectroscopic techniques were utilized to investigate the complex relationship between stereochemistry and aromaticity as well as to explore their unique electronic and geometric features. Finally, the potential for these heterocyclic motifs to be utilized for medicinal chemistry was evaluated by synthesizing an analogue of enzalutamide featuring the heterocyclic core and determining its resulting pharmacokinetic properties and bioactivity.

The first total syntheses of pseudorigidols A and B are reported. Our syntheses employ a rhodium-catalyzed C-H insertion reaction to build the tricyclic core. The catalyst screen revealed the influence of a remote stereogenic center on the diastereoselectivity of the insertion. Using two different catalysts, we were able to synthesize the two natural products with high diastereoselectivity. These results will lay the foundation for further studies on the influence of remote stereogenic centers.

Herein, we report the first asymmetric synthesis of cycloartobiloxanthone, a polycyclic dihydroxanthone natural product. Our convergent synthesis employs a rhodium-catalyzed C-H insertion reaction to construct the key fused tricyclic core with high enantioselectivity. Two fragments were joined together by a displacement reaction and a Friedel-Crafts acylation to generate the dihydroxanthone core. This synthesis offers a promising foundation for accessing structurally related dihydroxanthone natural products and analogues for structure-activity relationship studies.

A range of benzene and indole-fused carbocyclic molecules were accessed by the enantioselective C-H insertion of rhodium aryl/aryl carbenes. 1,4, 1,5, and 1,6 C-H insertion reactions are chemoselective for insertion into carbon centers appended with an electron-donating heteroatom. Examples include a range of ethers, a free hydroxyl group, and a range of nitrogen substituents, including basic amines. DFT calculations support a stepwise mechanism of this process and provide insight into the origin of both stereoselectivity and the preference for C-H versus O-H insertion.

The reactivity between sulfonimidamide-derived imines and cyclic anhydrides has been investigated. Sulfonimidamide imines readily react with homophthalic anhydride under mild conditions in the presence of non-nucleophilic bases to yield complex lactam products with high diastereoselectivity. Furthermore, it was discovered that sulfonimidamide imines react with homophthalic anhydride in the absence of a base to yield distinct diastereomer products with high diastereoselectivity. Density functional theory calculations suggest the existence of an open transition state pathway in the presence of base and a novel cyclic eight-membered transition state in the absence of base.

Herein we report the first transition metal-catalyzed approach to the enantioenriched synthesis of cyclic sulfonimidamides relying on commercially available palladium catalysts and ligands. High-throughput experimentation (HTE) was employed to identify the optimal catalyst system and solvent. The method is applied to a variety of saturated and unsaturated rings and exhibits the highest selectivity for 2-substituted allyl electrophiles. The products are further elaborated to complex, tricyclic scaffolds. DFT experiments presented herein highlight the key ligand substrate interactions leading to the high levels of enantioselectivity.

Two routes to assemble the complete tricyclic core of alopecurone C are described. In the first-generation route, an efficient synthesis of the "eastern" half of the target, including a decagram-scale rhodium-catalyzed C-H insertion reaction, was developed. When this route proved intractable for assembling the final flavanone ring, a successful second-generation route was developed from a flavanone precursor (naringenin) employing a later stage C-H insertion. Although the second route was ultimately unsuccessful for preparation of the final target, it does provide the basis for the efficient assembly of the complete tricyclic core of alopecurone C and related flavonostilbenoid natural products.

Correction for ‘Catalytic generation of ortho-quinone dimethides via donor/donor rhodium carbenes’ by Mingchun Gao et al., Chem. Sci., 2023, 14, 6443–6448, https://doi.org/10.1039/D3SC00734K.

A cost‐effective protocol has been used for the synthesis of novel benzo[g]benzo[4,5]imidazo[2,1-b]quinazoline derivatives. This domino, one‐pot, three‐component reaction was carried out between 2-hydroxy-1,4-naphthoquinone, aromatic aldehydes, and 2-aminobenzimidazole in the presence of piperidine in DMF solvent. This protocol has several advantages such as a convenient operational process, easy access to raw material, good yields and simple work-up. The structure of these compounds were characterized by spectroscopic techniques such as IR, 1H NMR, 13C NMR and CHN analysis.

Abstract EIF4E, an mRNA cap-binding protein, is necessary for cap-dependent translation. Overexpression of EIF4E is known to promote cancer development by preferentially translating a group of oncogenic mRNAs. Thus, 4EGI-1, a disruptor of EIF4E-EIF4G1 interaction, was developed to inhibit oncoprotein expression for cancer therapy. Interestingly, RBM38, an RNA-binding protein, interacts with EIF4E on TP53 mRNA, prevents EIF4E from binding to TP53 mRNA cap, and inhibits TP53 expression. Thus, Pep8, an eight amino acid peptide derived from RBM38, was developed to disrupt the EIF4E-RBM38 complex, leading to increased TP53 expression and decreased tumor cell growth. Herein, we have developed a first-in-class small-molecule compound 094, which interacts with EIF4E via the same pocket as does Pep8, dissociates RBM38 from EIF4E, and enhances TP53 translation in RBM38- and EIF4E-dependent manners. Structure-activity relationship studies identified that both the fluorobenzene and ethyl benzamide are necessary for compound 094 to interact with EIF4E. Furthermore, we showed that compound 094 is capable of suppressing three-dimensional tumor spheroid growth in RBM38- and TP53-dependent manners. In addition, we found that compound 094 cooperates with the chemotherapeutic agent doxorubicin and EIF4E inhibitor 4EGI-1 to suppress tumor cell growth. Collectively, we showed that two distinct approaches can be used together to target EIF4E for cancer therapy by enhancing wild-type TP53 expression (094) and by suppressing oncoprotein expression (4EGI-1).

Methodologies enabling the synthesis of enantioenriched sulfonimidamides containing a stereogenic sulfur center are scarce, often relying on diastereomeric crystallization or the use of chiral auxiliaries. The prototropic tautomerization exhibited by sulfonimidamides makes them uniquely suited for resolution processes. In the case where both nitrogen substituents of a disubstituted sulfonimidamide are the same, the two tautomers are also enantiomers, allowing deprotonation to generate a prochiral anion. Herein we report the first transition metal-catalyzed approach to the desymmetrization of sulfonimidamides relying on commercially available palladium catalysts and ligands. The reaction leads to functionalized, enantioenriched products in high yields.

Substrates engineered to undergo a 1,4-C–H insertion to yield benzocyclobutenes resulted in a novel elimination reaction to yield ortho¬-quinone dimethide (o-QDM) products that undergo Diels-Alder or hetero-Diels-Alder cycloadditions. The analogous benzylic acetals or ethers avoid the C–H insertion pathway completely and, after hydride transfer, undergo a de-aromatizing elimination reaction to o-QDM at ambient temperature. The resulting dienes undergo a variety of cycloaddition reactions with high diastereo- and regio-selectivity. This is one of the few examples of catalytic generation of o-QDM without the intermediacy of a benzocyclobutene and represents one of the mildest, ambient temperature processes to access to these useful intermediates. This proposed mechanism is supported by DFT calculations. Moreover, the methodology was applied to the synthesis of (±)-isolariciresinol in 42% overall yield.

Interactions between catalysts and substrates can be highly complex and dynamic, often complicating the development of models to either predict or understand such processes. A dirhodium(II)-catalyzed C-H insertion of donor/donor carbenes into 2-alkoxybenzophenone substrates to form benzodihydrofurans was selected as a model system to explore nonlinear methods to achieve a mechanistic understanding. We found that the application of traditional methods of multivariate linear regression (MLR) correlating DFT-derived descriptors of catalysts and substrates leads to poorly performing models. This inspired the introduction of nonlinear descriptor relationships into modeling by applying the sure independence screening and sparsifying operator (SISSO) algorithm. Based on SISSO-generated descriptors, a high-performing MLR model was identified that predicts external validation points well. Mechanistic interpretation was aided by the deconstruction of feature relationships using chemical space maps, decision trees, and linear descriptors. Substrates were found to have a strong dependence on steric effects for determining their innate cyclization selectivity preferences. Catalyst reactive site features can then be matched to product features to tune or override the resultant diastereoselectivity within the substrate-dictated ranges. This case study presents a method for understanding complex interactions often encountered in catalysis by using nonlinear modeling methods and linear deconvolution by pattern recognition.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

The Lewis acid catalyzed addition of prochiral E and Z allyl nucleophiles to chiral -alkoxy N-tosyl imines is described. Alkene geometry is selectively transferred to the newly formed carbon-carbon bond, resulting in stereochemical control of C2, C3, and C4 of the resulting 2-alkoxy-3-N-tosyl-4-alkyl-5-hexenes. The C3 and C4 diastereoselectivity (dr) is influenced by the geometry of the alkene, size of N-sulfonyl substituent, and steric bulk of the substituted -alkoxy ether group. This work demonstrates that three of the four possible diastereomers can be synthesized in high diastereoselectivity and high yields using the current methods. A mechanistic computational analysis to elucidate the high selectivity is also presented.