A generally applicable method for the synthesis of protected α‐oxygenated carbonyl compounds is reported. It is based on the single‐electron‐transfer oxidation of easily generated enolates to the corresponding α‐carbonyl radicals. Coupling with the stable free radical TEMPO provides α‐(piperidinyloxy) ketones, esters, amides, acids or nitriles in moderate‐to‐excellent yields. Enolate aggregates influence the outcome of the oxygenation reactions significantly. Competitive reactions have been analyzed and conditions for their minimization are presented. Chemoselective reduction of the products led to either N–O bond cleavage to α‐hydroxy carbonyl compounds or reduction of the carbonyl functionality tomonoprotected 1,2‐diols or O‐protected amino alcohols.

Cyclization/oxygenation and alkylation reactions: A concise total synthesis of 15‐F2t‐IsoP (see scheme) and its 15‐epimer, today used as the gold standard marker of oxidative stress in vivo, has been accomplished in 12 steps in 14 % overall yield by applying a vinylogous aldol addition, a new oxidative radical anion cyclization/oxygenation sequence to construct the cyclopentane core, and an acetylide alkylation as the key steps.

An 11-step total synthesis of the methyl ester of a potential metabolite of the autoxidatively formed natural product 15-E(2)-IsoP, whose metabolism is not known, is reported. Several vinylogous Mukaiyama aldol additions were tested for the assembly of the acyclic C7-C20 precursor. A new oxidative dianion cyclization served to access the cyclopentane core. The full carbon skeleton was synthesized by an acetylide alkylation. The overall yield of the metabolite amounts to 1.4% for the most efficient route. The results demonstrate convincingly that E(2)-IsoP metabolites are highly epimerization-sensitive and that they may thus also contribute to PGE(2)-action and metabolism.

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