The 12 Principles of Green Chemistry, established by Paul Anastas and John Warner in 1998, advocate for the design of inherently clean systems, prioritizing the prevention of waste, atom economy, and the minimization of derivatives, rather than focusing on remediation. Implementing such a framework necessitates the invention of innovative chemical transformations that fundamentally avoid byproduct formation. Dehydrogenative coupling, characterized by the evolution of dihydrogen (H₂) as the co-product, exemplifies these green chemistry ideals and stands as a compelling objective for the synthetic community. Following our 2020 discovery of the dehydrogenative coupling between aldehydes and alkylbenzenes to produce benzyl ketones, we have endeavored to broaden the reaction scope and uncover the fundamental mechanisms governing the unique selectivity. This article details our comprehensive investigations into these dehydrogenative coupling processes.

Photochemical reactions offer unique advantages, including spatiotemporal control, wavelength-selective activation, and in situ generation of highly reactive intermediates. In this paper, recent advances in photochemical transformations of small-membered cyclic carbonyl compounds, particularly cyclopropenones and cyclobutenediones, are summarized with a focus on the author’s contributions. Cyclopropenones serve as versatile precursors for reactive alkynes generated via photodecarbonylation. These alkynes enable diverse transformations such as click chemistry, dehydration condensations, and acyl radical-mediated processes. The use of aminocyclopropenones allows for light-controlled amide bond formation through transient ynamine intermediates, while alkoxy-substituted derivatives enable phototriggered ketene generation. Furthermore, photocatalytic strategies expand the usable wavelength range and enable chemoselective activation via photoredox or triplet energy transfer mechanisms. Cyclobutenediones, on the other hand, act as precursors of reversible bisketene intermediates. Their photochemical activation enables selective conjugation with acidic molecules, including carboxylic acids, phosphates, and sulfates, even under aqueous conditions. These reactions exhibit high chemoselectivity and potential applicability to biomolecular modification. Overall, small-membered cyclic carbonyl compounds provide unique reactivity profiles that can be harnessed for synthetic chemistry and chemical biology applications.

Bromine is an abundant elemental resource, and it has unique atomic properties leading to molecular functions and chemical techniques in and beyond synthetic organic chemistry. To exploit the high potential of bromine, catalytic methodologies are necessary for controlling the selectivity of bromination. However, conventional bromination tools are tolerated to a limited part of synthetic reactions due to the high reactivity, and the poor biocompatibility has disturbed the application to life science research. We developed bromination catalysts featuring a strained carbon-carbon double bond as the catalytic site, together with a brominating reagent bearing a carbon-bromine bond and a π-conjugated system, for applications in chemical biology via biocompatible catalytic bromination. We also found the utility of the strained olefin as a bromine scavenger, offering an alternative strategy for optimizing catalyst-controlled selectivity during bromination for organic synthesis. These reaction tools were designed using active sites bearing carbon platforms, which have high affinity with bromine and allow flexible molecular design, for controlling kinetics of bromination.

The direct catalytic asymmetric aldol reaction is a powerful method for constructing β-hydroxy carbonyls and 1,2-amino alcohols. However, the use of less acidic substrates at the carboxylic acid oxidation state, such as amides and esters, has remained challenging. To address this, we developed a cooperative catalyst system based on the soft Lewis acid/hard Brønsted base concept. Combination of a soft Cu(I) Lewis acid with chiral phosphine ligand and a hard Brønsted base of phenoxide enables stereoselective enolization under mild conditions.

This article reviews this catalyst design. We began with thioamides, developing the 1st generation catalyst (cooperative use of soft Lewis acid, copper with chiral phosphine ligand (R,R)-Ph-BPE and Brønsted base, Li salt of phenol), and lithium-free 2nd generation catalyst where the Cu-aldolate acts as a Brønsted base. We then expanded this concept to α-alkylamides and α-vinylacetamides by utilizing a 7-azaindoline directing group. Finally, we applied this cooperative copper catalysis to glycine Schiff bases, achieving highly syn-selective aldol reactions with broad substrate generality. This methodology provides syn-β-hydroxy-α-amino esters with excellent stereoselectivity and is currently being applied to the total synthesis of Nocathiacin I, as well as the commercial production of Fmoc-protected chiral amino acid building blocks.

Ecteinascidin 743 is a clinically used marine natural product that exerts potent antitumor activity through DNA alkylation and subsequent ternary complex formation with nuclear proteins. This review summarizes its biosynthesis, total synthesis, and mode of action, while highlighting our scaffold redesign strategy aimed at transforming this structurally complex natural product into a programmable medium-sized macrocyclic molecular platform. By replacing the native C1-C4 macrolactone bridge with C1-C5-bridged macrolactams, a series of 14-17-membered redesigned macrocycles were rapidly synthesized from cyanosafracin B through divergent semisynthesis. Systematic analyses of DNA alkylation, DNA double-strand break induction, and antiproliferative activity demonstrated that subtle macrocycle modifications can modulate biological activity and mode of action while preserving the key DNA-alkylating function of the core scaffold. These findings highlight scaffold redesign as a promising strategy for expanding the chemical and functional space of bioactive natural products.