A direct dehydroxylative allylation reaction of benzylic alcohols with allylsilanes catalyzed by Brønsted acids in 1,1,1,3,3,3-hexafluoro-2-propanol was developed. A wide variety of secondary and tertiary benzylic alcohols are applicable to the reaction with various allyltrimethylsilanes, to provide the corresponding coupling products in high yields. Using this catalytic transformation, a concise and short-step synthesis of (±)-crucudiol was achieved.

Cell-penetrating peptides (CPPs) have been widely applied as carriers in drug delivery systems (DDS) capable of transporting diverse biomolecules, including nucleic acids and highly hydrophilic low-molecular-weight compounds, into cells. Amphipathic CPPs composed of arginine and the α,α-disubstituted amino acid Aib (2-aminoisobutyric acid) have been investigated for their potential application as carrier peptides. In addition, the incorporation of d-amino acids into CPPs has been utilized as a strategy to confer resistance against proteolytic degradation, which is one of the major challenges associated with CPPs. In this study, we evaluated the structure, membrane permeability, and plasmid DNA (pDNA) delivery capability of (Arg–Arg–Aib)_n peptides with different combinations of l/d-Arg residues. Secondary structures were analyzed by circular dichroism (CD) spectroscopy, and their correlation with membrane permeability was examined. Consequently, α-helical peptides exhibited enhanced membrane permeability with increasing peptide chain length. In comparison between the same chain length of α-helical peptides and random-coil peptides, the difference in membrane permeabilities decreased as the peptide chain length increased. Notably, the peptide (l-Arg–d-Arg–Aib)₄ exhibited the highest protease resistance despite containing l-Arg residues and demonstrated pDNA transfection efficiency comparable to that of an α-helical peptide composed entirely of d-Arg residues. Optimization of l/d-Arg combinations for membrane permeability and gene delivery efficiency in (Arg–Arg–Aib)_n is useful for rationally designing amphipathic CPPs with l/d-amino acids.

Artemisinin derivatives (ARTs) induce ferrous iron-dependent cell death (ferroptosis) by generating free radicals. Polymer-ARTs conjugates would be advantageous for cancer therapy. In this paper, we designed and synthesized the three types of ART-conjugated novel methacrylamide derivatives with or without a spacer between the aromatic group and the methacrylamide moiety for mechanochemical solid-state polymerization. The polymer conversion rate of ART-ethyl-MA and ART-methyl-MA for 90 min polymerization was achieved at 78 and 49%, respectively. However, ART-MA, which does not have a spacer, could not polymerize owing to the lowest unoccupied molecular orbital (LUMO) expanding from the methacrylamide moiety to the aromatic sites. The resulting poly(ART-ethyl-MA) produced the thermodynamically stable end-chain radicals through the main-chain scission via mechanical energy, and the generated mechanoradicals would play a role as an initiator of the surrounding monomers. The biocompatible sulfobetaine polymer-ARTs conjugates were fabricated through the mechanochemical solid-state copolymerization of sulfobetaine methacrylate (SBMA) and ART-ethyl-MA. The number average molecular weight and heterogeneity of the resulting water-soluble PSBMA-ARTs conjugates were 8000 g mol^–1 and 1.10, respectively. These results suggest that the design of solid monomers suitable for mechanochemical solid-state polymerization would require a molecular structure susceptible to single solid-state electron transfer (SSET) and the stability of mechanoradicals generated by the main-chain scission of resulting polymer. The mechanochemical solid-state copolymerization of zwitterionic monomer and hydrophobic monomer would be advantageous for the development of biocompatible polymer–drug conjugates.

Highly strained small-ring heterocycles have recently attracted considerable attention as three-dimensional alternatives to planar aromatic motifs in medicinal chemistry. Among these, 1-azabicyclo[1.1.0]butanes (ABBs) represent an exceptionally compact nitrogen-containing scaffold with potential utility as precursors to heterocyclic bioisosteres. Nevertheless, general and modular synthetic approaches to ABBs remain scarce. Herein, we report a concise three-step route to C3-substituted ABBs from readily accessible azetidinones. Central to this strategy is an intramolecular 3-exo-tet cyclization triggered by deprotonation with organolithium reagents, proceeding efficiently at low temperature. The method accommodates a broad range of aryl substituents with diverse electronic properties. In addition, vinyl chloride-containing substrates undergo tandem cyclization and elimination, enabling direct access to previously unreported alkynyl-substituted ABBs. Although ABB formation is highly efficient, the resulting compounds exhibit limited stability, leading to rapid decomposition during purification. To clarify the factors governing this behavior, density functional theory (DFT) calculations were performed. Comparison of strain and protonation energies across a series of ABB derivatives revealed that differences in intrinsic ring strain are minimal and cannot account for the observed instability. Instead, protonation energy calculations suggest that protonation promotes heterolytic cleavage of the central C–N bond, generating a benzylic cation whose stability is strongly influenced by substituent electronics. A pronounced linear correlation between calculated protonation energies and Hammett σ parameters supports a dominant role of resonance stabilization.

The copper-catalyzed azide–alkyne cycloaddition (CuAAC) is a representative click reaction with practical applications in various fields, including medicinal chemistry. Its product, 1,4-disubstituted triazoles, has an elongated, rod-like shape. The continued proliferation of 1,4-disubstituted triazole-based drug candidates is concerning because existing bioactive compounds are heavily biased toward rod-like shapes with limited structural diversity, even though three-dimensional compounds generally possess more favorable druglike properties. Replacing this triazole ring with a 1,5-disubstituted counterpart is expected to bend the molecular shape and address these limitations. Here, to evaluate this possibility, we constructed a new library in which the triazole rings of our previously established 7-azanorbornane-based 1,4-disubstituted triazole library were replaced with 1,5-disubstituted counterparts. We then assessed the effects of this change on molecular shape, aqueous solubility, and membrane permeability. Ruthenium-catalyzed azide–alkyne cycloaddition (RuAAC), the most common synthetic method for 1,5-disubstituted triazoles, failed to produce the designed compounds, likely due to steric hindrance around the bicyclic scaffold. We therefore employed the reaction between acetylides and azides, which is relatively tolerant to steric hindrance, and successfully obtained the target 1,5-disubstituted triazoles, although not all designed compounds were produced. The 1,5-disubstituted triazoles synthesized here exhibited more three-dimensional shapes, greater structural diversity, and improved aqueous solubility than their 1,4-disubstituted counterparts, although no clear difference was observed in membrane permeability. These results suggest that replacing the triazole rings in CuAAC-derived libraries with 1,5-disubstituted counterparts is a promising strategy to construct libraries that exhibit greater three-dimensional structural diversity, and are more soluble in aqueous media.