The synthesis of (±)-(1R,6R,7R)-2-azabicyclo[4.2.0]octan-7-ol

Original Research http://ophcj.nuph.edu.ua UDC 547.717:547.712.22 D. A. Nosyk1,2,3, S. Yu. Lukyanenko2, D. S. Granat2,3, O. O. Yurchenko1,2, O. O. Grygorenko2,3,4 Institute of Organic Chemistry of the National Academy of Sciences of Ukraine, 5 Academician Kukhar str., 02094 Kyiv, Ukraine 2 Enamine Ltd., 78 Winston Churchill str., 02094 Kyiv, Ukraine 3 Taras Shevchenko National University of Kyiv, 60 Volodymyrska str., 01601 Kyiv, Ukraine 4 Enamine Scientific Research Institute, 67 Winston Churchill str., 02094 Kyiv, Ukraine 1 Synthesis of (±)-(1R,6R,7R)-2-azabicyclo[4.2.0]octan-7-ol Abstract An approach to the synthesis of (±)-(1R,6R,7R)-2-azabicyclo[4.2.0]octan-7-ol, a promising amino alcohol building block for drug discovery, has been described. The method is based on [2+2] the cycloaddition of tert-butyl vinyl ether and a ketene generated in situ from a glutaric acid derivative, as well as the intramolecular lactam formation as the key steps. Although the [2+2] cycloaddition step and further transformations proceeded without any notable stereoselectivity, the title compound was synthesized in an amount greater than 30 g with a high diastereomeric purity. This was provided by the physical properties of the intermediate (±)-(1R,6R,7R)-7-(tert-butoxy)-2-azabicyclo[4.2.0]octan-3-one that was easily separated by crystallization. Keywords: bicyclic compounds; [2+2] cycloaddition; lactams; building blocks Д. А. Носик1,2,3, С. Ю. Лук’яненко2, Д. С. Гранат2,3, О. О. Юрченко1,2, О. О. Григоренко2,3,4 1 Інститут органічної хімії Національної академії наук України, вул. Академіка Кухаря, 5, м. Київ, 02094, Україна 2 ТОВ НВП «Єнамін», вул. Вінстона Черчилля, 78, м. Київ, 02094, Україна 3 Київський національний університет імені Тараса Шевченка, вул. Володимирська, 60, м. Київ, 01601, Україна 4 НУ «НДІ «Єнамін», вул. Вінстона Черчилля, 67, м. Київ, 02094, Україна Синтез (±)-(1R,6R,7R)-2-азабіцикло[4.2.0]октан-7-олу Анотація Описано підхід до синтезу (±)-(1R,6R,7R)-2-азабіцикло[4.2.0]октан-7-олу – перспективного будівельного блока класу аміноспиртів для пошуку лікарських засобів. Метод ґрунтується на [2+2] циклоприєднанні трет-бутилвінілового етеру та кетену, що було генеровано in situ з похідної глутарової кислоти, а також внутрішньомолекулярному утворенні лактаму як ключових стадіях. Хоча стадія [2+2] циклоприєднання та подальші перетворення відбувалися без помітної стереоселективності, цільову сполуку було одержано в кількості понад 30 г з високою діастереомерною чистотою, що забезпечили фізичні властивості проміжного (±)-(1R,6R,7R)-7-(трет-бутокси)-2-азабіцикло[4.2.0]октан-3-ону, який легко відділяли кристалізацією. Ключові слова: біциклічні сполуки; [2+2] циклоприєднання; лактами; будівельні блоки Citation: Nosyk, D. A.; Lukyanenko, S. Yu.; Granat, D. S.; Yurchenko, O. O.; Grygorenko O. O. Synthesis of (±)-(1R,6R,7R)-2azabicyclo[4.2.0]octan-7-ol. Journal of Organic and Pharmaceutical Chemistry 2026, 24 (1), 23 – 28. https://doi.org/10.24959/ophcj.26.353627 Received: 1 February 2026; Revised: 18 March 2026; Accepted: 27 March 2026 Copyright© 2026, D. A. Nosyk, S. Yu. Lukyanenko, D. S. Granat, O. O. Yurchenko, O. O. Grygorenko. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0). Funding: The work was supported by Enamine Ltd. and Enamine CF. O. O. G. received funding from the Ministry of Education and Science of Ukraine, grant No. 25BF037-01 (0125U002249). Conflict of interests: The authors are employees or consulting scientists at Enamine Ltd. that offers the compounds described in the company’s catalog. ISSN 2308-8303 (Print) / 2518-1548 (Online) 23 Журнал органічної та фармацевтичної хімії 2026, 24 (1) ■ Introduction Saturated azabicyclic compounds have attracted much attention in organic and medicinal chemistry as promising three-dimensional chemotypes for drug discovery and other applications [1, 2]. They can be considered as conformationally restricted isosteres of piperidine, which is a top saturated heterocycle encountered in marketed drugs [3, 4]. 2-Azabicyclo[4.2.0]octane (1) is a representative of such bicyclic systems that can be found in a number of biologically active compounds (Figure 1). Notable examples include Bruton tyrosine kinase inhibitor 2 [5], acetylcholine esterase (AChE) inhibitor 3 [6], or chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) antagonist 4 [7]. Despite these success stories, efficient synthetic approaches towards properly functionalized 2-azabicyclo[4.2.0]octane derivatives are scarce. Thus, 7-functionalized derivative 5 was prepared by the Norrish type II reaction of N-tosyl piperidinyl ketone 6 (Scheme 1, A) [8]. 6‑Substituted isomers 7 were synthesized by the intramolecular [2+2] cycloaddition involving keteniminium salt intermediates (Scheme 1, B) [9]. Recently, our group reported the synthesis of 6-functionalized 2-azabicyclo[3.2.0] heptane derivatives based on the [2+2] cycloaddition of tert-butyl vinyl ether and a ketene generated in situ from a cinnamic acid derivative, as well as the intramolecular lactam formation as the key steps [10]. In this work, we report an extension of this methodology to 7-substituted 2-azabicyclo[4.2.0]octane derivatives. We demonstrate the applicability of this approach by the preparation of (±)-(1R,6R,7R)-2-azabicyclo[4.2.0]octan-7-ol (8) – a promising amino alcohol building block for drug discovery (Scheme 2). Notably, none of the literature approaches described in Scheme 1 is applicable to the synthesis of building block 8. Meanwhile, favorable physicochemical properties of compound 8 (the molecular weight MW = 175, the calculated 1-octanol – the water partition coefficient logarithm for a model N-acetyl derivative cLogP = –0.75) and three-dimensional, sp3rich, conformationally restricted nature make it a promising building block for the compound library synthesis in drug discovery. ■ Results and discussion Our synthesis of compound 8 started with the reaction of methyl 5-chloro-5-oxopentanoate (11) and tert-butyl vinyl ether (12) in the presence of Et3N in toluene at 110 °C (Scheme 3). The ketene N O N N H 2-Azabicyclo[4.2.0]octane (1) N N O N H O Me N O HN H H Cl H O H S N O O F OH N N BTK inhibitor 2 IC50 < 1 nM O N F F O CRTh2 antagonist 4 IC50 = 3.9 nM AChE inhibitor 3 IC50 = 0.1 mM Figure 1. Biologically active 2-azabicyclo[4.2.0]octanes A OH hν N B N R2 Et2O 6 N Ts 5 H 1. Tf2 pyridine, CHCl3 O R1 Ts O 2. LiAlH(Ot-Bu)3 R1 = Me, Ph, R2 = H, Me or R2/R3 = (CH2)n N R2 H R1 7 Scheme 1. The known approaches to the synthesis of 2-azabicyclo[4.2.0]octanes 24 ISSN 2308-8303 (Print) / 2518-1548 (Online) Journal of Organic and Pharmaceutical Chemistry 2026, 24 (1) H H OH OtBu OtBu O O N H H 8 OtBu + O N H H 9 Cl O 10 O O O 11 12 Scheme 2. The retrosynthetic analysis of amino alcohol 8 intermediate generated from acyl chloride 11 upon the action of Et3N reacted w (...truncated)