Generation and application of Cu-bound alkyl nitrenes for the catalyst-controlled synthesis of cyclic ß-amino acids.

The advent of saturated N-heterocycles as valuable building blocks in medicinal chemistry has led to the development of new methods to construct such nitrogen-containing cyclic frameworks. Despite the apparent strategic clarity, intramolecular C-H aminations with metallonitrenes have only sporadically been explored in this direction because of the intractability of the requisite alkyl nitrenes. Here, we report copper-catalysed intramolecular amination using an alkyl nitrene generated from substituted isoxazolidin-5-ones upon N-O bond cleavage. The copper catalysis exclusively aminates aromatic C(sp2)-H bonds among other potentially reactive groups, offering a solution to the chemoselectivity problem that has been troublesome with rhodium catalysis. A combined experimental and computational study suggested that the active species in the current cyclic ß-amino acid synthesis is a dicopper alkyl nitrene, which follows a cyclisation pathway distinct from the analogous alkyl metallonitrene.

Lewis Base Assisted Lithium Brønsted Base Catalysis: A New Entry for Catalytic Asymmetric Synthesis of ß2,2-Amino Acids.

A new catalytic system comprising chiral Ag complex and Li aryloxide/bisphosphine oxide is developed for the synthesis of ß2,2-amino acids via direct asymmetric Mannich-type reaction of 4-subsituted isoxazolidin-5-ones. The Mannich adduct is a direct precursor of ß-peptidic compounds otherwise difficult to obtain.

Catalytic asymmetric synthesis of CF3-substituted tertiary propargylic alcohols via direct aldol reaction of α-N3 amide.

Organofluorine compounds are found in several important classes of chemicals, such as pharmaceuticals, agrochemicals, and functional materials. Chemists have been immensely interested in the development of methodologies for expeditious access to fluorine containing building blocks. In this study, we report a new method for the catalytic asymmetric synthesis of CF3-substituted tertiary propargylic alcohols with two contiguous stereogenic centers via the direct aldol reaction of an α-N3 amide to trifluoromethyl ketones. The key to the success of this method is the identification of a catalyst comprising Cu(ii)/chiral hydroxamic acid to promote the desired aldol reaction, constructing a tetrasubstituted carbon in a highly stereoselective fashion. Despite substantial prior advances in asymmetric catalysis, this class of catalysts has not been utilized for the formation of carbon-carbon bond-forming reactions. Our mechanistic study sheds light on the unique profile of this catalytic system, where the Cu(ii) complex plays a bifunctional role of serving as a Lewis acid and a Brønsted base. Furthermore, the densely functionalized aldol adducts undergo chemoselective transformations, affording a series of fluorine containing chiral building blocks with widespread application.

Synthesis and Determination of Absolute Configuration of Lentztrehalose A.

The synthesis of lentztrehalose A, a naturally occurring trehalose derivative exhibiting various biological activities including autophagy-inducing activity, was achieved. The synthesis commenced with the selective protection of hydroxyl groups of commercially available trehalose, followed by the introduction of the side chain moiety by two methods: 1) prenylation and successive diastereoselective dihydroxylation; or 2) etherification by opening of the chiral epoxide. The present synthetic study clarified the unreported absolute configuration of the secondary alcohol part in the side chain portion.