Brønsted acid-catalyzed annulation reaction of hydroxamic acids: synthesis of cyclopentane-fused isoxazolidines and their benzilic amide rearrangement.

Readily available hydroxamic acids were leveraged to access challenging nitrones in the presence of H3PO4 as a Brønsted acid catalyst and engaged in an intramolecular (3+2) annulation reaction to make valuable cyclopentane-fused isoxazolidines with high yields and excellent diastereoselectivity. The products were further utilized in a unique base-promoted benzilic amide rearrangement to provide cyclopentane-fused γ-lactams bearing three contiguous stereocenters as a single diastereomer.

Organocatalyzed Modular Synthesis of Polycyclic Dihydropyridines and Pyridines through Sulfamate Linchpin.

The cascade annulation between alkylidene malononitriles and cyclic sulfamidate imines has been controlled by leveraging the sulfamate functionality under organocatalysis, which allows selective access to polycyclic and densely functionalized dihydropyridines and pyridines in high yields. The protocol is scalable and shows broad substrate scope. The products were also engaged in the preparation of tetracyclic pyridopyrimidines, showcasing the synthetic versatility.

Diastereoselective access to [4,4]-carbospirocycles: governance of thermodynamic enolates with an organocatalyst in vinylogous cascade annulation.

A vinylogy concept driven annulation strategy is developed to access [4,4]-carbospirocycles from alkylidene malononitriles and cyclopentene-1,3-diones. The reaction is catalyzed by an inexpensive organocatalyst and products with three stereocenters were obtained as a single diastereomer in high yields. The spiro-selectivity originates from the reaction of the thermodynamic enolate intermediate which is fundamentally intriguing.

Unorthodox cascade reaction of arynes and N-nitrosamides leading to indazole scaffolds.

An unusual cascade annulation of arynes with N-alkyl-N-nitrosamides is developed by leveraging aryne σ-insertion and C(sp3)-H bond functionalization strategies under transition-metal-free conditions at ambient temperature, offering functionalized indazoles in high yields and regioselectivity. The protocol is scalable and exhibits a broad substrate scope. The reaction mechanism is also studied with DFT calculations.

Annulation Cascade of Sulfamate-Derived Cyclic Imines with Glycine Aldimino Esters: Synthesis of 1,3-Benzoxazepine Scaffolds.

An efficient (3 + 2) cycloaddition triggered annulation is reported to access 1,3-benzoxazepine frameworks. With amine base, sulfamate-derived cyclic imines readily react with glycine aldimino esters to furnish benzo-fused seven-membered heterocyclic products in good yields. The cascade reaction involves the formation of one C-C, one C-N, and one C-O bond along with the cleavage of two C-N bonds and one S-O bond. The synthesis of o-tyrosine analogues has also been accomplished from annulation products.

Catalyst-Controlled Regioselective Nitrosocarbonyl Aldol Reaction of Deconjugated Butenolides.

An unprecedented regiodivergent nitrosocarbonyl aldol reaction of γ-substituted deconjugated butenolides is described. While Lewis base catalyst quinidine leveraged O-selective nitrosocarbonyl aldol reaction exclusively at the γ-position of deconjugated butenolides to produce γ-aminoxylation products, Lewis acid catalyst Cu(OTf)2 steered the competitive N-selective nitrosocarbonyl aldol reaction at the ß-position, resulting in heterodifunctionalized butenolides. Both processes were amenable to a broad range of substrates and scalable, while the latter one represents a rare example of one-pot hetero-ß,γ-difunctionalization of butenolide scaffolds.

Catalytic Regiodivergent Dearomatization Reaction of Nitrosocarbonyl Intermediates with ß-Naphthols.

The divergent reactivity of nitrosocarbonyls in oxidative dearomatization of ß-naphthols is reported. In the presence of quinidine catalyst, their reactions with α-unsubstituted ß-naphthols proceeded through the N-center to furnish α-imino-ß-naphthalenones in high yields. Upon exposure to α-substituted ß-naphthols in the presence of copper catalyst, an alteration of regioselectivity was observed to produce α-aminoxylation products. The reaction is scalable, tolerates a wide spectrum of functional groups, and represents a rare example of dearomatization of α-unsubstituted ß-naphthols.

Oxidative cross-dehydrogenative [2 + 3] annulation of α-amino ketones with α-keto esters: concise synthesis of clausenamide analogues.

A one-pot oxidative cross-dehydrogenative [2 + 3] annulation of α-amino ketones with α-keto esters at room temperature is reported. The protocol features copper/organo cooperative catalysis and provides densely functionalized pyrrolones in high yields. Subsequent reduction furnished multi-substituted pyrrolidinones which represent the core-structure of the natural product clausenamide, a lead molecule for the treatment of Alzheimer's disease.

Cross-Aldol Reaction of Activated Carbonyls with Nitrosocarbonyl Intermediates: Stereoselective Synthesis toward α-Hydroxy-ß-amino Esters and Amides.

A practical and flexible strategy toward α-hydroxy-ß-amino esters and amides, which are important biological motifs, based on an organocatalytic cross-aldol reaction of in situ-generated nitrosocarbonyl intermediates followed by hydrogenation is presented. The protocol features operational simplicity, high yields, a wide substrate scope, and high regio- and diastereoselectivity profiles. The utility of this method was showcased through the synthesis of bestatin analogues and indole formation.

Advanced Nitroso Aldol Reaction: Metal-Free Cross-Coupling of Anilines with Silyl Enol Ethers en Route to α-Amino Ketones.

A practical and step-economical nitroso aldol reaction has been developed based on metal-free direct cross-coupling of ready-stock anilines with silyl enol ethers at room temperature affording α-amino ketones in high yields (up to 82%). The protocol features a one-pot cascade of nitroso compound generation, selective C-N bond formation, and N-O bond cleavage using solely inexpensive and user-friendly Oxone and displays remarkable functional group tolerance. The method was further extended to prepare densely functionalized indoles that are otherwise difficult to synthesize.