Piperidinones, formation

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. 

The reaction can be alternatively carried out with TMSC1 as a Lewis acid and oiganocuprates [53]. (—)-Dihydro-pinidine, the enantiomer of an alkaloid from Pinas jeffrei, has been synthesized in excellent overall yield following this method. Piperidinone 46a was treated with Gilman s cuprate and trimethylsilylchloride in THF at -78 °C, such that the 2,6-disubstituted piperidinone 49a was obtained in high yield and diastereoselectivity. Its carbonyl group was reduced in a two-step procedure via formation of the dithiolane and subsequent desulfurization with Raney nickel. 

The fused azepine 29 was formed unexpectedly by the cyclisation of the Al-arylsulfonyl caprolactam 28 as a competing reaction for the formation of the alkcnylphosphonite 30 <07OBC3472>. The cyclisation was also specific for the seven-membered derivatives, with pyrrolidinone and piperidinone derivatives yielding the phosphonites as the only products. The mechanism is believed to be initial ortho-lithiation followed by nucleophilic addition to the lactam followed by dehydration. 

Ketone-type enamine substrates have also been utilized, as demonstrated through the synthesis of ( )-Na-benzyl-20-desethylaspidospermidine (45, P-H) from 43 (eq. 10).20 Treatment with methyl acrylate (37) resulted in conjugate addition to the acrylate and deallylation, and subsequent reduction with NaBH4 gave 44 as a 70 30 mixture of P a diastereomers. Reduction with L1AIH4 gave 45 (75 25, P a). However, similar stepwise aza-annulation with the enamine derived from pyrrolidine and a protected 4-piperidinone resulted in only 14% product formation.21... 

Treatment of -substituted 2-piperidinones with i-BuLi leads to the formation of the lithium amide enolates. These may be converted into zinc enolates with ZnCl2, which undergo C-C-cross-coupling with aryl bromides, e.g., as shown in (eq 62). 

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