Practical Multigram Approach to Conformationally Constrained α-Proline-Based Building Blocks with γ-Spiro Conjunction

Ievgenii A. Iermolenko; Oleksii S. Kolosov; Eugeniy N. Ostapchuk; Dmitry A. Lega; Nikita O. Derkach; Kostiantyn V. Levchenko; Valeriya G. Makhankova; Alexandr B. Rozhenko; Dmytro M. Volochnyuk; Serhiy V. Ryabukhin

doi:10.1055/a-2413-6896

Synthesis, Inhaltsverzeichnis

Synthesis 2025; 57(03): 664-674
DOI: 10.1055/a-2413-6896

paper

Practical Multigram Approach to Conformationally Constrained α-Proline-Based Building Blocks with γ-Spiro Conjunction

Ievgenii A. Iermolenko

^aEnamine Ltd., 78 Winston Churchill str., 02094 Kyiv, Ukraine

^cInstitute of Organic Chemistry of the National Academy of Sciences of Ukraine, 5 Akademik Kukhar str., 02094 Kyiv, Ukraine

,

Oleksii S. Kolosov

^aEnamine Ltd., 78 Winston Churchill str., 02094 Kyiv, Ukraine

,

Eugeniy N. Ostapchuk

^aEnamine Ltd., 78 Winston Churchill str., 02094 Kyiv, Ukraine

^bTaras Shevchenko National University of Kyiv, 60 Volodymyrska str., 01033 Kyiv, Ukraine

,

Dmitry A. Lega

^aEnamine Ltd., 78 Winston Churchill str., 02094 Kyiv, Ukraine

^bTaras Shevchenko National University of Kyiv, 60 Volodymyrska str., 01033 Kyiv, Ukraine

,

Nikita O. Derkach

^aEnamine Ltd., 78 Winston Churchill str., 02094 Kyiv, Ukraine

,

Kostiantyn V. Levchenko

^aEnamine Ltd., 78 Winston Churchill str., 02094 Kyiv, Ukraine

,

Valeriya G. Makhankova

^aEnamine Ltd., 78 Winston Churchill str., 02094 Kyiv, Ukraine

^bTaras Shevchenko National University of Kyiv, 60 Volodymyrska str., 01033 Kyiv, Ukraine

,

Alexandr B. Rozhenko

^bTaras Shevchenko National University of Kyiv, 60 Volodymyrska str., 01033 Kyiv, Ukraine

^cInstitute of Organic Chemistry of the National Academy of Sciences of Ukraine, 5 Akademik Kukhar str., 02094 Kyiv, Ukraine

,

Dmytro M. Volochnyuk∗

^aEnamine Ltd., 78 Winston Churchill str., 02094 Kyiv, Ukraine

^bTaras Shevchenko National University of Kyiv, 60 Volodymyrska str., 01033 Kyiv, Ukraine

^cInstitute of Organic Chemistry of the National Academy of Sciences of Ukraine, 5 Akademik Kukhar str., 02094 Kyiv, Ukraine

,

Serhiy V. Ryabukhin ∗

^aEnamine Ltd., 78 Winston Churchill str., 02094 Kyiv, Ukraine

^bTaras Shevchenko National University of Kyiv, 60 Volodymyrska str., 01033 Kyiv, Ukraine

^cInstitute of Organic Chemistry of the National Academy of Sciences of Ukraine, 5 Akademik Kukhar str., 02094 Kyiv, Ukraine

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Abstract

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Dedicated to all the brave defenders of Ukraine, whose sacrifice made this publication possible.

Abstract

Unusual amino acids have arisen as an indispensable instrument at the disposal of modern medicinal chemistry. While extensively exploited as building blocks in the search for new pharmaceuticals, their application goes far beyond. They are currently involved in explorations of the structure and conformational mobility of peptides, modification and amplification of peptidomimetic activity, and others. Herein, we report an effective synthetic approach to nonplanar, conformationally restricted, sp³-enriched spirocyclic α-prolines. The protocol employs readily available nitrile-based starting materials and conventional experimental procedures. The synthetic sequence is concise and includes three principal stages (one of them a four-step telescopic process). The reactions proceed on a multigram scale affording the target prolines in overall good yields. The possibility of chiral separation of the synthesized racemic spiro prolines to both pure enantiomers is shown. The building blocks synthesized in the study are expected to have practical uses in the field of medicinal chemistry.

Key words

amino acids - proline - spiro compounds - multigram - building blocks - medicinal chemistry - conformational rigidity

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