Rare cis-configured 2,4-disubstituted 1-alkylpiperidines: synthesized and tested against trace-amine-associated receptor 1 (TAAR1)

Levashova, Ekaterina; Firsov, A. V.; Bakulina, Olga; Peshkov, Anatoly A.; Kanov, Evgeny V.; Gainetdinov, Raul R.; Krasavin, Mikhail

doi:10.1016/j.mencom.2021.07.016

Cited by 6 publications

(4 citation statements)

References 9 publications

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“…Unsaturated 3-arylglutaconic acid anhydrides 89 react with imines to yield the corresponding lactones that decarboxylate in the reaction medium to form 2-piperidinones 90 . Subsequent stereoselective hydrogenation and lactam reduction produce challenging cis -configured 1,2,4-trisubstituted piperidines 91 ( Scheme 31 ) [ 62 , 63 ]. In addition, 3-Arylglutaconic acid anhydrides can also react with unprotected oximes to produce the corresponding N -hydroxylactams [ 64 ].…”

Section: Two-component Castagnoli–cushman Reactions (2c-ccr)mentioning

confidence: 99%

The Castagnoli–Cushman Reaction

et al. 2023

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Since the first reports of the reaction of imines and cyclic anhydrides by Castagnoli and Cushman, this procedure has been applied to the synthesis of a variety of lactams, some of them with important synthetic or biological interest. The scope of the reaction has been extended to the use of various Schiff bases and anhydrides as well as to different types of precursors for these reagents. In recent years, important advances have been made in understanding the mechanism of the reaction, which has historically been quite controversial. This has helped to develop reaction conditions that lead to pure diastereomers and even homochiral products. In addition, these mechanistic studies have also led to the development of new multicomponent versions of the Castagnoli–Cushman reaction that allow products with more diverse and complex molecular structures to be easily obtained.

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Section: Two-component Castagnoli–cushman Reactions (2c-ccr)mentioning

confidence: 99%

The Castagnoli–Cushman Reaction

et al. 2023

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“…Finally, lactam-to-amine reduction was achieved using lithium aluminum hydride in ether. 15 The reaction also proceeded smoothly over 24 h at room temperature and the expected spirocyclic piperidine 6a was isolated in 93% yield (Scheme 2 ).…”

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confidence: 97%

“…The initial decarboxylative Castagnoli–Cushman reaction (CCR) was conducted under the previously developed conditions 14 and gave a satisfactory 75% yield. Subsequent non-autoclave hydrogenation of compound 4a , thus obtained, over 10% Pd/C, proceeded cleanly and gave full conversion to the fully saturated lactam 5a in 24 h; 15 the latter was isolated in an excellent 92% yield. Finally, lactam-to-amine reduction was achieved using lithium aluminum hydride in ether.…”

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confidence: 98%

A General Approach to Spirocyclic Piperidines via Castagnoli–Cushman Chemistry

et al. 2022

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Unsaturated spirocyclic lactams stemming from a variant of the three-component Castagnoli–Cushman reaction successfully underwent hydrogenation to enable access to fully saturated spirocyclic lactams. The subsequent lactam reduction gave rise to 2-spiro piperidine building blocks. The latter can be further elaborated in compound libraries and, on their own, show propensity to activate trace amine-associated receptor 1 (TAAR1), an important target for CNS disease.

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“…We reasoned that the unconjugated double bond in adducts 13 could be further manipulated either by hydrogenation 17–25 or base-promoted isomerization into the α,β-unsaturated N -hydroxylactams. 17 Indeed, carboxylic acid-containing product 13d was smoothly hydrogenated to give an excellent yield of cis -configured 25 saturated N -hydroxy-2-piperidone 20 . This is a notable result, considering that N -hydroxylactams are prone to the loss of the hydroxy group under reductive conditions.…”

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confidence: 99%