none 10.1002/anie.202304246 Wiley Wiley (John Wiley & Sons) 311 148176389 89 2024012121383000944 10.1002 2024-01-22T05:43:53Z 2023-05-26T10:53:52Z 99 Angewandte Chemie International Edition Angew Chem Int Ed 1433-7851 1521-3773 09 25 2023 62 39 10.1002/anie.v62.39 https://onlinelibrary.wiley.com/toc/15213773/62/39 Dmitry Dibchak Enamine Ltd. Chervonotkatska 60 02094 Kyiv Ukraine Mariya Snisarenko Enamine Ltd. Chervonotkatska 60 02094 Kyiv Ukraine Artem Mishuk Enamine Ltd. Chervonotkatska 60 02094 Kyiv Ukraine Oleh Shablykin Enamine Ltd. Chervonotkatska 60 02094 Kyiv Ukraine Institute of Bioorganic Chemistry and Petrochemistry National Academy of Sciences of Ukraine Akademika Kukharya, 1 02094 Kyiv Ukraine Lina Bortnichuk Bienta Chervonotkatska 78 02094 Kyiv Ukraine Oleksii Klymenko‐Ulianov Bienta Chervonotkatska 78 02094 Kyiv Ukraine Yurii Kheylik Bienta Chervonotkatska 78 02094 Kyiv Ukraine Iryna V. Sadkova Enamine Ltd. Chervonotkatska 60 02094 Kyiv Ukraine Henry S. Rzepa Department of Chemistry Molecular Sciences Research Hub White City Campus Imperial College London 82 Wood Lane London W12 0BZ UK Pavel K. Mykhailiuk Enamine Ltd. Chervonotkatska 60 02094 Kyiv Ukraine http://orcid.org/0000-0003-1821-9011 Abstract A general approach to 3‐azabicyclo[3.1.1]heptanes by reduction of spirocyclic oxetanyl nitriles was developed. The mechanism, scope, and scalability of this transformation were studied. The core was incorporated into the structure of the antihistamine drug Rupatidine instead of the pyridine ring, which led to a dramatic improvement in physicochemical properties. 06 15 2023 09 25 2023 e202304246 10.1002/anie.202304246 2 10.1002/crossmark_policy onlinelibrary.wiley.com true 2023-03-27 2023-06-15 HORIZON EUROPE European Research Council https://doi.org/10.13039/100019180 101000893 http://creativecommons.org/licenses/by/4.0/ 10.1002/anie.202304246 https://onlinelibrary.wiley.com/doi/10.1002/anie.202304246 https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.202304246 10.1038/s41586-022-05290-z   10.1021/jacs.2c09733 10.1021/jacs.2c11501 10.1021/jacs.2c13740   10.1038/s41557-023-01222-0 10.1002/anie.202000548 10.1021/acs.joc.8b02071 For recent reviews on bioisosteric replacements of the phenyl ring see 10.1039/C8OB02812E 10.1021/acs.jmedchem.1c01215   10.3987/COM-88-S10 10.1002/anie.200806394 10.1021/ol101866x 10.1002/adsc.201400571 Synlett Tymtsunik A. 0355 25 2014 10.1002/ejoc.202000733 10.1016/j.bmcl.2014.06.081   10.1002/anie.201703801 10.1039/D1SC03615G 10.1002/chem.201702362 10.1002/chem.201800193   10.1021/ja809176m 10.1021/acs.orglett.2c00564 10.1021/acs.orglett.1c03419 10.1021/acs.orglett.0c02729 10.1021/acs.orglett.9b03810 10.1021/acs.joc.5b01255 10.1021/ja00542a041   10.1002/anie.202004183 10.1021/acs.orglett.2c03606 10.1038/s41467-022-33827-3 10.1038/s41586-022-04636-x   10.1126/science.aad6252 10.1021/jacs.6b13229 10.1021/jacs.7b11865 10.1039/C8SC01355A 10.1021/jacs.1c04180 10.1002/anie.202213508 10.1021/jacs.2c05304 10.1038/s41557-022-00979-0 10.1002/anie.201909655 10.1038/s41586-020-2060-z 10.1021/acs.orglett.0c02017 10.1002/anie.201914875 10.1021/jacs.1c10541 10.1002/anie.201706799 10.1002/anie.202205103 10.1002/anie.202214507 10.1038/s41557-023-01135-y 10.1021/jacs.2c09248 10.1021/jacs.2c02976 10.1002/anie.202204719 10.1055/s-0036-1588733 Deposition Numbers2226166 (3a⋅HCl) 2237707 (11a⋅HCl) 2237706 (15a⋅HCl) 2237705 (45)contain the supplementary crystallographic data for this paper. These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum KarlsruheAccess Structures service. 10.1016/S0040-4039(01)88749-9 For full details of the calculations see D. Dibchak M. Snisarenko A. Mishuk O. Shablykin L. Bortnichuk O. Klymenko-Ulianov Y. Kheylik I. Sadkova H. S. Rzepa P. K. Mykhailiuk Imperial College research data repository 2022 FAIR Datahttps://doi.org/10.14469/hpc/11474. 10.1126/science.aan3679 10.1107/S2056989021000979 https://go.drugbank.com/drugs/DB11614(accessed on 23. 03. 2023). https://www.drugs.com/uk/rupafin-10mg-tablets-leaflet.html(accessed on 23. 03. 2023). clogPwas calculated with “Cxcalc” (ChemAxon version 22.5.0). Nitrogen atom inNMe-piperidine pKa(Base⋅HCl)=10 is notably more basic than that in pyridine pKa(Base⋅HCl)=5. This should be kept in mind during the possible bioisosteric replacements. 10.26434/chemrxiv-2023-jbb0r This work was originally deposited at a preprint server ChemRxiv:https://doi.org/10.26434/chemrxiv-2023-jbb0r.