Diverse N,N,O-trisubstituted hydroxylamines, an under-represented group in compound collections, are readily prepared by partial reduction of N-acyloxy secondary amines with diisobutylaluminum hydride followed by acetylation and reduction of the so-formed O-acyl-N,N-disubstituted hydroxylamines with triethylsilane and boron trifluoride etherate. Use of carbon nucleophiles in the last step, including allyltributylstannane, silyl enol ethers, and 2-methylfuran, gives N,N,O-trisubstituted hydroxylamines with branching α- to the O-substituent. N,N-Disubstiuted hydroxylamines are conveniently prepared by reaction of secondary amines with dibenzoyl peroxide followed by diisobutylaluminum hydride reduction.

The influence of the electron-withdrawing azide group on the reduction of O-(1-acyloxy-ω-azido)hydroxylamines by triethylsilane in the presence of boron trifluoride etherate is studied and found to increase with increasing proximity to the reaction site, suggesting that the reaction proceeds by way of aminoxocarbenium ion intermediates. The ability to carry azides through the reaction sequence affords O-(ω-azidoalkyl-N,N-dialkylhydroxylamines thereby making such functionality available for use in click chemistry. A series of 4-substituted N-alkoxypiperidines were prepared and studied by variable temperature NMR spectroscopy leading to the conclusion that the rate-determining step in the stereomutation of such piperidines is the piperidine ring flip and not nitrogen inversion or rotation about the N-O bond. The process of N-O bond rotation only becomes rate determining when in the presence of pervasive steric hindrance as is the case with the N-alkoxy-2,2,6,6-tetramethylpiperidines.

We describe the synthesis of 10-aza-9-oxakalkitoxin, an N,N,O-trisubstituted hydroxylamine-based analog, or hydroxalog, of the cytotoxic marine natural product kalkitoxin in which the -NMe-O-moiety replaces a -CHMe-CH 2 -unit in the backbone of the natural product. 10-Aza-9-oxakalkitoxin displays potent and selective cytotoxicity (IC 50 2.4 ng mL −1 ) comparable to that of kalkitoxin itself (IC 50 3.2 ng mL −1 ) against the human hepato-carcinoma cell line HepG2 over both the human leukemia cell line CEM and the normal hematopoietic CFU-GM. Like kalkitoxin, and contrary to the common expectation for hydroxylamines, 10-aza-9-oxakalkitoxin is not mutagenic.

Diastereoselective oxidative coupling of ketones through a silyl bis-enol ether intermediate by anodic and photocatalytic oxidation is reported. These methods provide several 1,4-diketones in good yields without the need for stoichiometric metal oxidants. The strategic use of a silicon tether enables the coupling of both aromatic and aliphatic ketones as well as the synthesis of quaternary centers. Cyclic voltammetry is used to gain insight into the oxidation events of the reaction.

An efficient sequence for preparation of the title compounds, a hitherto under‐represented class of compounds, from readily available starting materials is designed.