α,β-Unsaturated Diazoketones as Versatile Building Blocks for the Synthesis of Hydroxylated Piperidines, Indolizidines and Quinolizidines

Abstract

A four-step approach for the synthesis of dihydroxylated piperidine, quinolizidine and indolizidine systems is described employing α,β-unsaturated diazoketones as versatile building blocks. Unsaturated diazoketones were readily prepared from a Horner-Wadsworth-Emmons reaction between a diazophosphonate and amino-aldehydes. The strategy employs an asymmetric dihydroxylation reaction as the key step and is simple and straightforward enough to be extended to other nitrogen heterocycles.

α,β-Unsaturated Diazoketones as Useful Platforms in the Synthesis of Nitrogen Heterocycles

“…35 From the studies described in Scheme 14, we decided to perform the synthesis of more complex indolizidines, such as hydroxylated indolizidines and castanospermine analogues as well as quinolizidines. 36,37 Nitrogen heterocycles bearing hydroxyl groups (aza-sugars) are well-known for their ability to act as potent αand β-glycosidase inhibitors and have been used for many years in chemical biology. One of the key points in the synthesis of compounds for biological studies is to guarantee access to many analogues from a single synthetic methodology or chemical intermediate.…”

“…The preparation of octahydroindolizidin-8-ols 19 constitutes a formal synthesis of pumiliotoxin 251D. 36 The same synthetic sequence described above could also be applied in the synthesis of chiral dihydroxylated piperidines, 37 employing an amino-aldehyde derived from glycine or ethanolamine. In this case, Sharpless asymmetric dihydroxylation was employed, which permitted the preparation of both enantiomers in 92% enantiomeric excess.…”

“…In all the cases where Z and E mixtures were obtained, the isomers could be separated by a simple column chromatography . As depicted in Figure , several α,β-unsaturated α-diazoketones could be prepared in scales up to 1.0 g by our methodology, including complex and chiral ones. ,,− It is worth mentioning that the method is direct and uses aldehydes, which are well-known for being easy to prepare and available from several suppliers.…”

“…As a part of our studies employing α,β-unsaturated diazoketones for the synthesis of nitrogen heterocycles, we also decided to prepare several indolizidines, quinolizidines and piperidines, with the nitrogen atom already attached to these diazoketones (at the γ-position; Figure ). − To accomplish that, amino-aldehydes were the reagents of choice, since they are easy to prepare and would provide the diazoketones directly from our methodology. In this sense, a diazoketone such as 13 would possess all of the carbons necessary to construct 6-membered rings (after necessary functionalizations).…”