2H-Azirines, the smallest nitrogen-containing heterocycle possessing high ring strain energy, have been investigated for many decades in view of both biological activities of themselves and their unique reactivities ascribed to the strain release. Their synthetic potential has been recognized again in this century, and various types of their synthetic methods and transformation reactions especially involving metal-catalyzed methodology have been reported. Herein, we describe historical developments and recent trends on the synthesis and transformation of 2H-azirines classified into reaction types. We also summarize recent papers on catalytic asymmetric synthesis concerning 2H-azirines as an important topic.

We have developed a method for catalytic site-selective acylation of various glucose derivatives, which enables to deliver acyl groups at the secondary C(4)-OH in the presence of the free primary C(6)-OH. Under these catalyst-controlled conditions, the reaction takes place with reversal of the intrinsic reactivity. Based on this protocol, unconventional retrosynthetic analysis for total synthesis of natural glycosides was proposed: (1) final-stage site-selective introduction of a p-coumaroyl group into the unprotected natural glycoside precursors for total synthesis of multifidosides A-C, (2) site-selective and sequential introduction of galloyl groups into unprotected glucose for extremely short step total synthesis of ellagitannins.

In the context of drug design, C-H…O hydrogen bonds have received little attention so far, mostly because they are considered weak relative to other noncovalent interactions. Herein, we demonstrate the significance of hydrogen bonds between C-H groups adjacent to an ammonium cation and an oxygen atom (N⁺-C-H…O hydrogen bonds) in protein-ligand complexes. Quantum chemical calculations revealed the strength and geometrical requirements of these N⁺-C-H…O hydrogen bonds, and a subsequent survey of the Protein Data Bank based on the quantum chemical calculation results suggested that numerous protein-ligand complexes contain such N⁺-C-H…O hydrogen bonds. An ensuing experimental investigation into enzyme inhibitor complexes demonstrated that N⁺-C-H…O hydrogen bonds affect the activity of ligands against their target proteins. In addition, we identified histone demethylase inhibitors designed based on the formation of N⁺-C-H…O hydrogen bonds between them and their target protein. These results should provide the basis for the use of N⁺-C-H…O hydrogen bonds in drug discovery.

Chiral phosphine oxides successfully catalyze asymmetric cross-aldol reactions between various two carbonyl compounds in highly enantioselective manners. The hypervalent silicon complex formed from chiral phosphine oxide catalysts and chlorosilanes, sequentially activates aldol donors and acceptors to facilitate the aldol reactions in the presence of base amines. The combination of a chiral phosphine oxide with silicon tetrachloride mediates regioselective silyl enolization of diketones to realize highly enantioselective asymmetric intramolecular aldol reaction. Sequential activation of carbonyl compounds with the hypervalent silicon complex facilitates asymmetric branched-type and linear-type double aldol reactions to realize one-pot construction of up to four stereogenic centers.

The direct asymmetric aldol reaction of activated ketones is a useful method for synthesizing optically active tertiary alcohols, which are convenient synthetic intermediates. The active use of effective asymmetric catalysts in this reaction has been reported; however, asymmetric catalysts with a broad substrate scope for this reaction are limited. In this paper, we have summarized our research on the development of effective tailor-made tripeptide catalysts for this reaction using various activated ketones as substrates. Useful asymmetric catalysts could be developed for the direct asymmetric aldol reaction of isatins and trifluoromethyl ketones by fine-tuning the C-terminal amino acid in the tripeptide catalyst having glycine adjacent to proline. H-Pro-Gly-D-Ala-OH (3c) was employed to catalyze the reaction between isatins and acetone to afford the corresponding aldol adduct in up to 99% yield and 97% ee. The reaction between trifluoromethyl ketones and acetone, catalyzed by H-Pro-Gly-Ala-OH (3b), afforded the corresponding aldol adduct in up to 81% yield and 77% ee. Conversely, for the reaction of α-ketoesters with acetone, H-Pro-Tle-Gly-OH (3m) displayed the best catalytic activity and enantioselectivity. The 3m-catalyzed reaction between α-ketoesters and acetone yielded aldol adducts in up to 95% yield and 88% ee. In addition, the origins of enantioselectivity for the 3c-catalyzed reaction of isatins and the 3m-catalyzed reaction of α-ketoesters were disclosed by the analysis of the C-C bond-formation step using density functional theory (DFT) calculations.

The ceramide compound, N-((2S,3R)-1,3-dihydroxyoctadecan-2-yl)stearamide (D-erythro-CER [NDS]), plays a critical role for the barrier function of mammalian skin. This material is widely used for various cosmetics and drugs for the skin care purpose. The development of an efficient synthetic route for optically active D-erythro-CER [NDS] using continuous flow synthesis and purification techniques is described. The route proceeds through asymmetric transfer hydrogenation of methyl 2-acetamido-3-oxooctadecanoate in a Pipes-in-Series flow reactor with oxo-tethered ruthenium complex “DENEB^®”-catalyzed dynamic kinetic resolution as a key process. The subsequent continuous processes including the crystallization and crystal separation were also investigated. This synthesis was accomplished without isolating any intermediates, allowing for the consecutive synthesis and purification on a production scale.

Ladderane is a class of molecules having ladder-fused polycyclobutane backbones which are also found in bacterial membrane lipids. The unique structures containing polycyclobutane or its related moieties have been attractive synthetic targets, while also offer interesting properties including self-assembly and cascade unzipping, which would be applicable to future mechanoresponsive smart materials.