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Carbonyl compounds employed as carbon nucleophiles have played a dominant role in synthetic organic chemistry; however, there is very limited use of these compounds as oxygen nucleophiles. In particular, there are only a few reports on the oxy-Michael addition of the enol forms of carbonyl nucleophiles. In this study, we present the asymmetric cycloetherification of enols, which are generated in situ from enone-bearing ketones, using chiral bifunctional organocatalysts bearing amino and squaramide groups. This transformation chemo-and enantioselectively afforded dihydropyran derivatives, which are the core structures of building blocks for synthesizing glycans.

Organocatalysts activate substrates through mild noncovalent and covalent interactions, and their cooperative actions at multiple catalytic sites are essential even in intrinsically rapid organic reactions such as intramolecular cyclizations. The enzyme-like catalytic system is effective for recognizing specific molecular conformations of substrates, which continually change under reaction conditions, through multipoint interactions, thereby leading to high stereoselectivity. On the basis of this concept, we developed a range of organocatalytic asymmetric synthetic reactions, which are challenging using other categories of catalysts. The proposed catalysis was applied to various manners of asymmetric induction including those accompanied by not only facial selectivity but also by kinetic resolution (KR), dynamic kinetic resolution (DKR), desymmetrization, and dynamic kinetic asymmetric transformation (DYKAT). They enabled various asymmetric transformations through intramolecular hetero-Michael addition, construction of axial chirality, and alpha, beta-unsaturated acylammonium catalysis, which advanced the methods for asymmetric heterocycle synthesis, construction of tetrasubstituted chiral carbons, enantioselective synthesis of axially chiral compounds, and asymmetric library synthesis of pharmaceutically potential compounds. This study also expanded the chemistry of bifunctional organocatalysis. This review provides a comprehensive account of our achievements regarding multipoint recognition of molecular conformations with organocatalysts for asymmetric synthetic reactions.

Enantioselective bromination of axially chiral cyanoarenes bearing high intrinsic rotational barriers via dynamic kinetic resolution using bifunctional organocatalysts is reported. Sequential addition of a brominating reagent in several portions at an optimized temperature was effective in accomplishing high enantioselectivities.

Enantioselective approaches to synthesize six-membered oxacycles with multiple stereogenic centres are in high demand to enable the discovery of new therapeutic agents. Here we present a concise organocatalytic cycloetherification for the highly enantio- and diastereoselective synthesis of tetrahydropyrans involving simultaneous construction of two chiral centres, one of which is fully substituted. This method involves dynamic kinetic resolution of reversibly generated chiral cyanohydrins. A chiral bifunctional organocatalyst selectively recognizes a specific chair-like conformation of the intermediate, in which the small steric effect of the linear cyano group as well as its anomeric effect play important roles in controlling stereoselectivity. The products offer additional utility as synthetic intermediates because the cyano group can be further transformed into a variety of important functional groups. This strategy provides a platform to design efficient approaches to obtain a wide range of optically active tetrahydropyrans, which are otherwise synthetically challenging materials.

A novel method of enantioselective 1, 3-dioxane construction via a hemiacetalization/intramolecular oxy-Michael addition cascade by a chiral phosphoric acid catalyst was developed. The product was successfully transformed into an optically active 1, 3-polyol motif, indicating that the proposed reaction can provide useful chiral building blocks for the de novo synthesis of polyketides.

Chiral oxacyclic frameworks are prevalent in many natural products and bioactive compounds. In addition, a number of them are important synthetic intermediates. Thus, the synthesis of such structures is a significant goal in the field of organic chemistry. However, the development of catalytic asymmetric cycloetherification for the straightforward synthesis of these compounds remains a challenge. In this study, we propose the use of aminothiourea catalysis as an effective way to accomplish such a challenge. The asymmetric synthesis of chiral oxygen heterocycles, including tetrahydrofurans, tetrahydropyrans, and 1, 3-dioxolanes, is demonstrated herein using intramolecular oxy-Michael addition mediated by bifunctional aminothiourea catalysts.