The first chemical method for selective dual sp(3) C-H functionalization at the alpha-and beta positions of cyclic amines to their corresponding 3-alkoxyamine lactams is reported. Unlike traditional Cα-H oxidation of amines to amides mediated by transition metals, the present protocol, which involves the use of NaClO2/TEMPO/NaClO in either aqueous or organic solvent, not only allows the Cα-H oxidation but also the subsequent functionalization of the unreactive β-methylene group in an unprecedented tandem fashion and using environmentally friendly reactants.

By using cheap and innocuous reagents, such as NaClO 2 , NaOCl, and catalytic amounts of TEMPO, a new environmentally friendly protocol for the selective and catalytic TEMPO C(sp 3 )−H oxidation of piperazines and morpholines to 2,3-diketopiperazines (2,3-DKP) and 3morpholinones (3-MPs), respectively, has been developed. This novel direct access to 2,3-DKP from piperazines provides significant advantages over the traditional N-monoacylation/ intramolecular C−N cyclization procedure. Additionally, by modulating the amounts of TEMPO, 2-alkoxyamino-3morpholinone can be prepared from morpholine derivatives, which would enable further functionalization at the C2 position of the morpholine skeleton.

The substrate-controlled asymmetric total synthesis and absolute configurational assignment of biologically active 3α,4α-epoxy-5β-pipermethystine, a minor component in the aerial parts of kava, has been achieved by featuring, as a key step, the environmentally friendly and direct synthesis of 2,3-epoxyamides from allyl amines. By using the chiron approach, first a carbohydrate-derived dehydropiperidine was prepared and subjected to a stereoselective tandem C-H/C[double bond, length as m-dash]C oxidation reaction. In this attempt, the required α,α-trans-epoxy-2-piperidone skeleton of the kava metabolite precursor was not achieved, although the tandem oxidation was highly stereoselective. However, starting from non-carbohydrate 3-hydroxy-4,5-dehydropiperidine, and using the same tandem oxidation, the target intermediate was obtained in high yield and complete unprecedented anti-stereoselectivity. Since the proposed mechanistic course of this tandem oxidation implies the transient formation of an α,β-unsaturated amide followed by the subsequent epoxidation reaction, this second approach supports the previously established biotransformation proposal of (-)-pipermethystine to (-)-3α,4α-epoxy-5β-pipermethystine.

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