Stereo- and Chemoselective Enrichment of sp3 Character in Post-Ugi Morpholines

Muhammad Hasan; Gulzat A. Nuroldayeva; Azamat Begenov; Anatoly A. Peshkov; Sofia D. Martynova; Niyaz Amire; Ainara Bekbolatova; Azat M. Makhmet; Jiafeng Yu; Manzoor Zaman; Jing Gong; Chang Keun Lim; Andrey Belyaev; Olga P. Pereshivko; Shunyi Wang; Vsevolod A. Peshkov

doi:10.1002/ejoc.202401124

Stereo- and Chemoselective Enrichment of sp³ Character in Post-Ugi Morpholines

Muhammad Hasan, Gulzat A. Nuroldayeva, Azamat Begenov, Anatoly A. Peshkov, Sofia D. Martynova, Niyaz Amire, Ainara Bekbolatova, Azat M. Makhmet, Jiafeng Yu, Manzoor Zaman, Jing Gong, Chang Keun Lim, Andrey Belyaev, Olga P. Pereshivko, Shunyi Wang, Vsevolod A. Peshkov

School of Engineering and Digital Sciences

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

Abstract

We conducted a systematic study on synthesis and modification of morpholine core using Ugi adducts derived from propiolic acid and glycolaldehyde dimer. The assembly step involved triphenylphosphine-promoted 6-exo-dig umpolung oxa-Michael cyclization of Ugi-derived hydroxypropargylamides yielding 2-methylenemorpholin-3-one derivatives. Subsequent heterogeneous catalytic hydrogenation of the exocyclic double bond proceeded in a highly diastereoselective fashion establishing a relative cis configuration in the resulting sp³-enriched morpholinone scaffold. Finally, chemoselective amide reduction with lithium aluminum hydride (LAH) allowed to obtain fully saturated morpholines while leaving the more sterically hindered exocyclic amide moiety intact. Taken together these findings outline the strategy for controlled reduction of the inherent rigidity of post-Ugi scaffolds.

Original language	English
Article number	e202401124
Journal	European Journal of Organic Chemistry
Volume	28
Issue number	4
DOIs	https://doi.org/10.1002/ejoc.202401124
Publication status	Published - Jan 24 2025

Keywords

chemoselectivity
diastereoselectivity
morpholines
post-Ugi transformations
sp-enriched heterocycles

ASJC Scopus subject areas

Physical and Theoretical Chemistry
Organic Chemistry

Access to Document

10.1002/ejoc.202401124

Cite this

Hasan, M., Nuroldayeva, G. A., Begenov, A., Peshkov, A. A., Martynova, S. D., Amire, N., Bekbolatova, A., Makhmet, A. M., Yu, J., Zaman, M., Gong, J., Lim, C. K., Belyaev, A., Pereshivko, O. P., Wang, S., & Peshkov, V. A. (2025). Stereo- and Chemoselective Enrichment of sp³ Character in Post-Ugi Morpholines. European Journal of Organic Chemistry, 28(4), Article e202401124. https://doi.org/10.1002/ejoc.202401124

Hasan, M, Nuroldayeva, GA, Begenov, A, Peshkov, AA, Martynova, SD, Amire, N, Bekbolatova, A, Makhmet, AM, Yu, J, Zaman, M, Gong, J, Lim, CK, Belyaev, A, Pereshivko, OP, Wang, S & Peshkov, VA 2025, 'Stereo- and Chemoselective Enrichment of sp³ Character in Post-Ugi Morpholines', European Journal of Organic Chemistry, vol. 28, no. 4, e202401124. https://doi.org/10.1002/ejoc.202401124

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abstract = "We conducted a systematic study on synthesis and modification of morpholine core using Ugi adducts derived from propiolic acid and glycolaldehyde dimer. The assembly step involved triphenylphosphine-promoted 6-exo-dig umpolung oxa-Michael cyclization of Ugi-derived hydroxypropargylamides yielding 2-methylenemorpholin-3-one derivatives. Subsequent heterogeneous catalytic hydrogenation of the exocyclic double bond proceeded in a highly diastereoselective fashion establishing a relative cis configuration in the resulting sp3-enriched morpholinone scaffold. Finally, chemoselective amide reduction with lithium aluminum hydride (LAH) allowed to obtain fully saturated morpholines while leaving the more sterically hindered exocyclic amide moiety intact. Taken together these findings outline the strategy for controlled reduction of the inherent rigidity of post-Ugi scaffolds.",

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AU - Yu, Jiafeng

AU - Zaman, Manzoor

AU - Gong, Jing

AU - Lim, Chang Keun

AU - Belyaev, Andrey

AU - Pereshivko, Olga P.

AU - Wang, Shunyi

AU - Peshkov, Vsevolod A.

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N2 - We conducted a systematic study on synthesis and modification of morpholine core using Ugi adducts derived from propiolic acid and glycolaldehyde dimer. The assembly step involved triphenylphosphine-promoted 6-exo-dig umpolung oxa-Michael cyclization of Ugi-derived hydroxypropargylamides yielding 2-methylenemorpholin-3-one derivatives. Subsequent heterogeneous catalytic hydrogenation of the exocyclic double bond proceeded in a highly diastereoselective fashion establishing a relative cis configuration in the resulting sp3-enriched morpholinone scaffold. Finally, chemoselective amide reduction with lithium aluminum hydride (LAH) allowed to obtain fully saturated morpholines while leaving the more sterically hindered exocyclic amide moiety intact. Taken together these findings outline the strategy for controlled reduction of the inherent rigidity of post-Ugi scaffolds.

AB - We conducted a systematic study on synthesis and modification of morpholine core using Ugi adducts derived from propiolic acid and glycolaldehyde dimer. The assembly step involved triphenylphosphine-promoted 6-exo-dig umpolung oxa-Michael cyclization of Ugi-derived hydroxypropargylamides yielding 2-methylenemorpholin-3-one derivatives. Subsequent heterogeneous catalytic hydrogenation of the exocyclic double bond proceeded in a highly diastereoselective fashion establishing a relative cis configuration in the resulting sp3-enriched morpholinone scaffold. Finally, chemoselective amide reduction with lithium aluminum hydride (LAH) allowed to obtain fully saturated morpholines while leaving the more sterically hindered exocyclic amide moiety intact. Taken together these findings outline the strategy for controlled reduction of the inherent rigidity of post-Ugi scaffolds.

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