Piperidinones, unsaturated

The same group expanded the scope of the aza-Diels-Alder reaction of electron-rich dienes to Brassard s diene 97 (Scheme 37) [60]. In contrast to Danishefsky s diene, it is more reactive, but less stable. Akiyama et al. found chiral BINOL phosphate (R)-3m (3 mol%, R = 9-anthryl) with 9-anthryl substituents to promote the [4 + 2] cycloaddition of A-arylated aldimines 94 and Brassard s diene 97. Subsequent treatment with benzoic acid led to the formation of piperidinones 98. Interestingly, the use of its pyridinium salt (3 mol%) resulted in a higher yield (87% instead of 72%) along with a comparable enantioselectivity (94% ee instead of 92% ee). This method furnished cycloadducts 98 derived from aromatic, heteroaromatic, a,P-unsaturated, and aliphatic precursors 94 in satisfactory yields (63-91%) and excellent enantioselectivities (92-99% ee). NMR studies revealed that Brassard s diene 97 is labile in the presence of phosphoric acid 3m (88% decomposition after 1 h), but comparatively stable in the presence of its pyridinium salt (25% decomposition after 1 h). This observation can be explained by the fact that the pyridinium salt is a weak Brpnsted acid compared to BINOL phosphate 3m. 

A novel one-pot tandem oxidation-cyclization-oxidation process was successfully applied in the transformation of unsaturated alcohols 250 [Eq. (5.315)].860 The intermediate aldehyde formed by oxidation with pyridinium chlorochromate (PCC) undergoes a carbonyl-ene cyclization followed by an additional oxidation to form 3-substituted piperidinones. 

Dienes in which the double bonds are separated by 4, 5, or 6 bonds, and linked through amine or amide functions, readily undergo RCM in the presence of various initiators to yield substituted unsaturated cyclic amines or amides (pyrrolidinones, piperidinones, piperidines) see Table 8.4. 

Conjugate additions to unsaturated piperidinones constitute an important method for the stereoselective generation of piperidines <01OL611>. Hayashi and co-workers have... 

Kurth and co-workers utihzed two 13DC reactions in the same sequence for the synthesis of bis-isoxazolo substituted piperidinone skeleton 214 (Scheme 51) [ 154]. The reaction sequence involved Michael addition of an unsaturated alkoxide 207 to j6-nitrostyrene 75a followed by INOC or ISOC. The resulting isoxazoline intermediate 209 was subjected to Grignard addition for the generation of the isoxazolidine moiety 211, which upon DCC-mediated coupling with nitroacetic ester 212 furnished the intermediate 213 bearing both nitroalkane and alkene moiety. This intermediate upon INOC reaction led to the bis-isoxazolo piperidinone nucleus 214. 

This section deals with oxidation reactions as an initiative step of the domino process in combination with many other organic transformations. In 2004, Snaith and coworkers [3] demonstrated a simple and efficient method to synthesize 3-substituted 4-piperidinones 4 using a domino oxidation/carbonyl-ene/oxidation reaction (Scheme 9.1). This domino reaction comprises oxidation of unsaturated alcohol 1 using PCC (pyridinium chlorochromate) to give the corresponding aldehyde 2, followed by a carbonyl-ene type reaction to yield the secondary cyclic alcohol 3, which was oxidized under the reaction conditions to give 3-substituted 4-piperidinones 4 in good yields. 

For example, formal synthesis of the antidepressive drug (-)-paroxetine 31 was achieved based on the iminium-ion-catalyzed conjugate/cyclization cascade reaction (Scheme 3.4) [20]. In the presence of catalyst 29, the reaction of amidomalonate 27 with a,P-unsaturated aldehyde 28 afforded the chiral piperidinone 30 with good results (84% yield, 90% ee, 5 1 dr). After further transformation, formal synthesis of the blockbuster antidepressive drug (-)-paroxetine 31 was achieved. 

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