Stereoselective Synthesis of Bioactive Compounds (Track)

Stereoselctive synthesis of functionalized piperidines via a Domino imino-aldol-aza-Michael reaction sequence

Manas K. Ghorai
Department of Chemistry, Indian Institute of Technology, Kanpur, 208016, India

Abstract:

Aza- and oxa-cycles, especially piperidines and pyrone moieties are very important subunits found in various natural products and bioactive molecules. Stereoselective synthesis of substituted piperidines and pyrones with high structural diversity is a real challenge for synthetic organic chemists. In continuation of our ongoing research activities in enolate and dianion chemistry, we have developed a new strategy for the synthesis of 6-membered nitrogen and oxygen containing ring systems via the regioselective addition of 1,3-dicarbonyl dianion derived from ethyl acetoacetate to N-activated imines and aldehydes.1 We have further utilized both the nucleophilic centers of ethyl acetoacetate for the formation of two consecutive C-C bonds. For this purpose, first a-arylmethylidine- or a-alkylidine-ß-keto esters were synthesized as the starting precursor compounds. We have developed a one-pot two step domino approach for the synthesis of highly functionalized 2,6-disubstituted piperidine-3-carboxylate ring system in good yield (upto 70%) and with excellent stereoselectivity (syn selectivity de >99%, ee >99%).2 The protocol involves (i) formation of enolate from the precursor substrates a-arylmethylidine- or a- alkylidine-ß-keto ester with the treatment of LDA followed by (ii) intermolecular imino-aldol reaction with N-activated imines and (iii) intramolecular aza-Michael reaction. 2,6-disubstituted piperidine-3-carboxylate moieties are pharmacologically very important and some molecules containing this ring system exhibit antitubercular and antibacterial activities.3

References:

1. Ghorai, M. K.; Kumar, A.; Halder, S. Tetrahedron 2007, 63, 4779.
2. Ghorai, M. K.; Halder, S.; Das, R. K. J. Org. Chem. 2010, 75, 7061.
3. Jeong, et. al. Bioorg. Med. Chem. Lett. 2008, 18, 6542.