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Synthesis 2022; 54(11): 2604-2615
DOI: 10.1055/s-0040-1719878
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A General Approach to Spirocyclic Piperidines via Castagnoli–Cushman Chemistry

Anatoly A. Peshkov
a   Institute of Chemistry, Saint Petersburg State University, 26 Universitetskii prospect, Peterhof, 198504, Saint Petersburg, 199034, Russian Federation
,
Azat Makhmet
a   Institute of Chemistry, Saint Petersburg State University, 26 Universitetskii prospect, Peterhof, 198504, Saint Petersburg, 199034, Russian Federation
b   L. N. Gumilyov Eurasian National University, Department of Chemistry, Faculty of Natural Sciences, Nur-Sultan, 010000, Kazakhstan
,
Olga Bakulina
a   Institute of Chemistry, Saint Petersburg State University, 26 Universitetskii prospect, Peterhof, 198504, Saint Petersburg, 199034, Russian Federation
,
Evgeny Kanov
c   Institute of Translational Biomedicine, St. Petersburg State University, 199034 St. Petersburg, Russian Federation
,
Raul Gainetdinov
c   Institute of Translational Biomedicine, St. Petersburg State University, 199034 St. Petersburg, Russian Federation
,
Vsevolod A. Peshkov
d   Nazarbayev University, Department of Chemistry, School of Sciences and Humanities, Nur-Sultan, 010000, Kazakhstan
,
Dmitry Dar’in
a   Institute of Chemistry, Saint Petersburg State University, 26 Universitetskii prospect, Peterhof, 198504, Saint Petersburg, 199034, Russian Federation
,
Mikhail Krasavin∗
a   Institute of Chemistry, Saint Petersburg State University, 26 Universitetskii prospect, Peterhof, 198504, Saint Petersburg, 199034, Russian Federation
e   Immanuel Kant Baltic Federal University, Kaliningrad 236016, Russian Federation
› Author AffiliationsThis research was supported by the Russian Science Foundation (grant no. 19-75-30008).
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Abstract

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.

Keywords

Castagnoli–Cushman - spirocyclic motifs - compound libraries - trace amine-associated receptor 1 agonists

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0040-1719878. Included are the copies of NMR spectra of all prepared compounds, the single-crystal XRD analysis data of 6c and 7b as well as the results of in vitro biological studies of compounds 6b, 6c, 6g and 6j.
  • Supporting Information


Publication History

Received: 08 October 2021

Accepted after revision: 13 December 2021

Article published online:
08 February 2022

© 2022. Thieme. All rights reserved

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