Stereoselective strategies for the construction of polysubstituted piperidinic compounds and their applications in natural products’ synthesis

Abstract

International audienceNitrogen-encompassing bioactive molecules can be regarded as the most frequently cited moieties, occurring either as natural products or as synthetically constructed chemical entities. One such framework which is abundantly found in both natural and synthetic chemical structures is the piperidinic core. A functionalized piperidinic core, either in natural products or in pharmaceuticals, is one of those immensely prevalent moieties. The piperidine frame can be seen in innumerable drug entities and this can be attributed to various reasons like the spacing obtained by piperidine structural conformers during the drug–receptor interactions, and solubility enhancement, hence resulting in improved pharmacokinetics and, most importantly, making the drug architecture metabolically stable. Further tapering down, 2, 4 and 6 substituted piperidines in general and with chiral centres in specific have attracted a substantial amount of attention in the recent past. This can be attributed to their diverse biological activities like analgesic, antimicrobial, sedative, antiasthmatic etc. In this communication, we aim to sum up and review all the reported methods since 2009 for the construction of the polysubstituted piperidinic core. Each method cited herein is exemplified with the synthesis of a natural compound and particularly alkaloids

A Stereoselective aza-Prins Reaction: Rapid Access to Enantiopure Piperidines and Pipecolic Acids

“…When using (3S,5S)-3-(3-Methylbut-2-enyl)-5-phenylmorpholin-2-one (8e, Table 5 entries 2- 4), the formation of a 5-membered ring was observed, presumably via the more stable tertiary carbocation, and irrespective of the aldehyde or acid employed. 17 (3S,5S)-3-(2-Methylallyl)-5-phenylmorpholin-2-one (8d, entries [5][6][7][8] gave a new single isomer quaternary chiral centre. Finally using (3S,5S)-5-Phenyl-3-(prop-2-ynyl) morpholin-2-one (8b, entry 9) gave a single vinyl halide-containing diastereoisomer and enantiomer where either Cl or Br could be incorporated into the product.…”

“…The vast majority of these drugs require careful stereocontrol of the substitutents around the ring during manufacture. Methods for their synthesis have been widely reviewed [2][3][4][5] but the greatest problem has always been the asymmetric construction of the piperidine ring. Furthermore, there is an emerging need for sp 3 -rich heterocyclic frameworks, again with both relative and absolute stereocontrol of the substituents.…”

The Ruthenium‐Catalyzed Domino Cross Enyne Metathesis/Ring‐Closing Metathesis in the Synthesis of Enantioenriched Nitrogen‐Containing Heterocycles

“…This is crucial in drug discovery, since opposing enantiomers may present very different biological activity . For this reason, great efforts have been invested in the development of novel synthetic strategies for the construction of enantioenriched nitrogen‐containing heterocycles throughout the past few decades . However, the emergence of alternative methodologies capable of easily constructing such target molecules remains scarce in medicinal and synthetic organic chemistry …”

Enantiodivergent Approach to the Synthesis of Cis-2,6-Disubstituted Piperidin-4-ones

“…In particular, systems with the piperidine skeleton having substituents at the 2- and 6-positions with a relative cis -configuration and a carbonyl or a hydroxyl group at 4-position are of special interest. Consequently, the asymmetric synthesis of these polysubstituted piperidine derivatives has attracted much attention that is reflected in the development of numerous strategies on that purpose . The most general methods involve as key steps of the synthesis of these compounds either an intramolecular condensation follow by reduction from the corresponding amino ketone derivative or an intramolecular allylic substitution, as depicted in Scheme A.…”