Piperidinones 2,6-disubstituted

The chiral piperidinones 46 formed by the reaction between Danishefsky s diene and the glycosyl imines are valuable synthons for the synthesis of higher substituted piperidine derivatives. 2,6-Disubstituted piperidinones 49 are obtained by addition of organocuprates complexes with boron trifluoride [53]. The reaction pathway is illustrated in Scheme 30. 

The cis 2,6 disubstituted piperidinones 49 are formed preferentially in this Michael-type addition reaction (Table 4.7). 

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. 

Intramolecular Mannich reactions have also been used in the synthesis of piperidines. An intramolecular Mannich reaction was applied as the key step in the synthesis of the piperidine A ring of cylindrospermopsin <07SL1446> and in the high yielding diastereoselective conversion of 3-amino acids to 2,6-yy -disubstituted piperidinones <07JOC10287>. 

Stereoselective Synthesis of 2 6-Disubstituted Piperidinones According to Scheme 10.65 (Ref. [136])... 

Further additions of soft nucleophiles to resin-bound dehydropiperidinones 5 were examined. Conversion with a cuprate reagent, R2Cu(CN)Li2, in the presence of BF3.OEt2 gave access to 2,6-disubstituted piperidinones with high structural... 

In 2005, Honda et al. pubhshed a first total synthesis of a quinohzidine alkaloid using RCM as one of the key steps, namely, (—)-deoxynupharidine (246) [80]. The alkaloid was isolated from plants of the genus Nuphar and exhibited amongst others immunosuppressive activity. Its synthesis commenced with a stereoselective construction of the enantiopure 5,6-disubstituted piperidinone building block 244 by modification and ring expansion of the protected D-pyroglutamic acid derivative 243 (Scheme 2.53). Subsequent RCM of 244 (catalyst [Ru]-II, benzene, 60°C) afforded quinolizidinone 245 in 96% yield, whereafter three consecutive steps led to the natural product itself... 

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