4-Azaspiro[2.3]hexane, an Overlooked Piperidine Isostere: Multigram Synthesis and Physicochemical and Structural Evaluation
An expedient approach to the synthesis of 4-azaspiro[2.3]hexane derivatives is described. The synthetic scheme consists of Tebbe olefination of <i>N</i>-Boc-protected 2-azetidinone (including the first use of the deuterated Petasis reagent Cp<sub>2</sub>Ti(CD<sub>3</sub>)<sub>2</sub> in the building block preparation) and cyclopropanation of the resulting intermediate. The developed protocols allowed for the preparation of target building blocks on a multigram scale (up to 52 g). To illustrate the potential of the obtained 4-azaspiro[2.3]hexane derivatives for isosteric replacements in drug discovery, their physicochemical and structural characterization was performed, i.e., basicity (p<i>K</i><sub>a</sub>) and lipophilicity (Log <i>P</i>) measurements, X-ray diffraction studies, and exit vector plot (EVP) analysis.
Authors
- Oleksandr S. Liashuk (ORCID: https://orcid.org/0000-0002-2677-435X)
- Oleksandr O. Grygorenko (ORCID: https://orcid.org/0000-0002-6036-5859)
- Denys V. Kliukovskyi
- Sergey V. Ryabukhin (ORCID: https://orcid.org/0000-0003-4281-8268)
- Anton V. Chernykh (ORCID: https://orcid.org/0000-0002-2292-4138)
- Dmitriy M. Volochnyuk (ORCID: https://orcid.org/0000-0001-6519-1467)
- Svitlana V. Shishkina (ORCID: https://orcid.org/0000-0002-3946-1061)
- Dmytro Lesyk (ORCID: https://orcid.org/0009-0001-3391-5165)
- Sergiy Galavskyy
Institutions
- National Academy of Sciences of Ukraine (UA)
- Taras Shevchenko National University of Kyiv (UA)
- Institute of Organic Chemistry (UA)
- Enamine (Ukraine) (UA)
Publication Details
- Journal
- The Journal of Organic Chemistry
- Published
- 2024-11-26
- DOI
- https://doi.org/10.1021/acs.joc.4c02390
- Citations
- 7
- Primary Topic
- Chemical Reaction Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 1.75
Funders
- Ministry of Education and Science of Ukraine
- Enamine