Functionalized Derivatives of 2-azaspiro[3.3]heptane-1-carboxylic Acid and 7-oxa-2-azaspiro[3.5]nonane-1-carboxylic Acid for Drug Design


  • Alexander Kirichok Department of Chemistry, Taras Shevchenko National University of Kyiv, Volodymyrska Street, 64/13, Kyiv 01601, Ukraine
  • Tatyana Yegorova



piperidine, azetidine, bioisoster, pipecolic acid, drug design


2-azaspiro[3.3]heptane-1-carboxylic acid and 7-oxa-2-azaspiro[3.5]nonane-1-carboxylic acid, which had been reported as bioisoster of well-known pipecolic acid, were subjected to chemical transformations, resulting in a number of functionalized derivatives. The obtained molecules contained diversified functional groups, allowing their incorporation in bioactive compounds in versatile modes. Described synthetic approaches afforded multigram-scaled synthesis of the desired compounds with good yields, thus being applicable in drug design


Lovering F, Bikker J, Humblet C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. Journal of Medicinal Chemistry 2009;52(21):6752-6756.

Mykhailiuk P. Saturated bioisosteres of benzene: where to go next? Organic & Biomolecular Chemistry 2019;17(11):2839-2849.

Locke G, Bernhard S, Senge M. Nonconjugated Hydrocarbons as Rigid‐Linear Motifs: Isosteres for Material Sciences and Bioorganic and Medicinal Chemistry. Chemistry – A European Journal 2019;25(18):4590-4647.

Frank N, Nugent J, Shire B, Pickford H, Rabe P, Sterling A, Zarganes-Tzitzikas T, Grimes T, Thompson A, Smith R, Schofield C, Brennan P, Duarte F, Anderson E. Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane. Nature 2022;611(7937):721-726.

Burkhard J, Wagner B, Fischer H, Schuler F, Müller K, Carreira E. Synthesis of Azaspirocycles and their Evaluation in Drug Discovery. Angewandte Chemie International Edition 2010;49(20):3524-3527.

Degorce S, Bodnarchuk M, Scott J. Lowering Lipophilicity by Adding Carbon: AzaSpiroHeptanes, a logD Lowering Twist. ACS Medicinal Chemistry Letters 2019;10(8):1198-1204.

Kirichok A, Shton I, Kliachyna M, Pishel I, Mykhailiuk P. 1‐Substituted 2‐Azaspiro[3.3]heptanes: Overlooked Motifs for Drug Discovery. Angewandte Chemie International Edition 2017;56(30):8865-8869.

Kirichok A, Shton I, Pishel I, Zozulya S, Borysko P, Kubyshkin V, Zaporozhets O, Tolmachev A, Mykhailiuk P. Synthesis of Multifunctional Spirocyclic Azetidines and Their Application in Drug Discovery. Chemistry – A European Journal 2018;24(21):5444-5449.

Cardellini F, Brinchi L, Germani R, Tiecco M. Convenient Esterification of Carboxylic Acids by SN2 Reaction Promoted by a Protic Ionic-Liquid System Formed in Situ in Solvent-Free Conditions. Synthetic Communications 2014;44(22):3248-3256.

Groth T, Meldal M. Synthesis of Aldehyde Building Blocks Protected as Acid Labile N-Boc N,O-Acetals: Toward Combinatorial Solid Phase Synthesis of Novel Peptide Isosteres. Journal of Combinatorial Chemistry 2000;3(1):34-44.

Dess D, Martin J. Readily accessible 12-I-5 oxidant for the conversion of primary and secondary alcohols to aldehydes and ketones. The Journal of Organic Chemistry 1983;48(22):4155-4156.

Seyferth D, Marmor R, Hilbert P. Reactions of dimethylphosphono-substituted diazoalkanes. (MeO)2P(O)CR transfer to olefins and 1,3-dipolar additions of (MeO)2P(O)C(N2)R. The Journal of Organic Chemistry 1971;36(10):1379-1386.

Bortolami M, Petrucci R, Rocco D, Scarano V, Chiarotto I. Alkynes as Building Blocks, Intermediates and Products in the Electrochemical Procedures Since 2000. ChemElectroChem 2021;8(19):3604-3613.

Dhameja M, Pandey J. Bestmann–Ohira Reagent: A Convenient and Promising Reagent in the Chemical World. Asian Journal of Organic Chemistry 2018;7(8):1502-1523.