An Improved Stereocontrolled Access Route to Piperidine or Azepane β‐Amino Esters and Azabicyclic β‐ and γ‐Lactams; Synthesis of Novel Functionalized Azaheterocyles

Abstract

An improved, efficient synthesis of some functionalized saturated azaheterocycles has been accomplished by controlled functionalization of various readily available cyclic compounds containing ring C=C bond. The stereocontrolled synthetic concept was based on the oxidative ring cleavage of various unsaturated scaffolds across ozonolysis followed by ring closing with double reductive amination with primary alkylamines or fluorinated alkylamines. The protocol provided versatile azaheterocyclic derivatives with a piperidine or azepane framework.

Selective Functionalizations of Cycloalkene‐Fused β‐Lactams and their Transformations into Densely‐Substituted Three‐Dimensional Molecular Entities

“…The procedure was based on the oxidation of the C=C double bond into the corresponding dialdehydes by ozonolysis (Scheme 11). [20] In a previous work, [19a] the dihydroxylation/diol cleavage/ reductive amination protocol of the N-Boc-protected β-lactam (37) showed low reactivity under the conditions used (Scheme 10). In contrast, applying the ozonolysis/reductive amination procedure the reaction was more successful.…”

“…purification was only necessary in the final step. [20] The ozonolysis/reductive amination method was performed with 2,2,2-trifluoroethylamine (Scheme 11). In contrast with the earlier work, [19] this reaction gave only two products: the known monocyclic diamino lactam 41 and piperidine-fused lactam 42 (Scheme 11).…”

“…The products were separated by column chromatography. [20] The reaction was extended with the use of other amines as well. The reaction protocol was identical with the method described in Scheme 11.…”

“…The procedure was based on the oxidation of the C=C double bond into the corresponding dialdehydes by ozonolysis (Scheme 11). [20] …”

Stereocontrolled Synthesis of Some Novel Azaheterocyclic β-Amino Ester Stereoisomers with Multiple Stereogenic Centers

“…These compounds exhibit various biological activities, and they can also serve as building blocks of bioactive foldamers (Figure 2). [12][13][14] Our research group has reported a number of selective and controlled synthesis pathways toward azaheterocyclic -amino esters, 8,[15][16][17][18][19][20][21][22][23] including a recent stereocontrolled method that utilized an RRM of N-allylated (or N-propargylated) norbornene -amino esters to prepare compounds with a hexahydro-1H-cyclopenta[b]pyridine scaffold. 8 The current publication extends this pathway to provide access to further stereoisomers, namely, hexahydro-1H-cyclopenta[b]pyridine derivatives and some analogues with a hexahydrofuro [3,2-b]pyridine scaffold.…”