Anton V Chernykh, Bohdan V Vashchenko, Svitlana V Shishkina, Dmytro M Volochnyuk, Oleksandr O Grygorenko
{"title":"3-取代的 6-氮杂双环[3.1.1]庚烷:用于药物发现的非经典哌啶异构体。","authors":"Anton V Chernykh, Bohdan V Vashchenko, Svitlana V Shishkina, Dmytro M Volochnyuk, Oleksandr O Grygorenko","doi":"10.1021/acs.joc.4c00326","DOIUrl":null,"url":null,"abstract":"<p><p>Advanced analogs of piperidine and smaller homologues of tropane─3-substituted 6-azabicyclo[3.1.1]heptanes─were synthesized on a large scale using readily available bulk reagents. The key step of the approach involved the double alkylation reaction of malonate with <i>cis</i>-2,4-bis(mesyloxymethyl)azetidine-1-carboxylate, in turn easily prepared on up to 1 kg scale. After hydrolysis, <i>N</i>-Boc-6-azabicyclo[3.1.1]heptane-3,3-dicarboxylic acid was obtained (up to 400 g in a single run), which was used as a common intermediate for the preparation of all the title building blocks. In particular, Pb(OAc)<sub>4</sub>-mediated oxidative decarboxylation of this intermediate gave 2,6-methanopiperidone derivative (up to 400 g scale), while monodecarboxylation gave <i>N</i>-Boc-6-azabicyclo[3.1.1]heptane-3-carboxylic acids as an easily separatable mixture of <i>cis</i> and <i>trans</i> diastereomers (up to 100 g scale). Further functional group transformations gave diastereopure <i>cis</i>- and <i>trans</i>-<i>N</i>-Boc-monoprotected diamines and amino alcohols. Molecular structure analysis using exit vector parameters (EVP) revealed that <i>cis</i> isomers of 3-substituted 6-azabicyclo[3.1.1]heptanes are three-dimensional analogs of common 1,4-disubstituted piperidine <i>chair</i> conformer, whereas <i>trans</i> isomers can be considered as unusual \"<i>boat</i>\" piperidines.</p>","PeriodicalId":57,"journal":{"name":"The Journal of Organic Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"3-Substituted 6-Azabicyclo[3.1.1]heptanes: Nonclassical Piperidine Isosteres for Drug Discovery.\",\"authors\":\"Anton V Chernykh, Bohdan V Vashchenko, Svitlana V Shishkina, Dmytro M Volochnyuk, Oleksandr O Grygorenko\",\"doi\":\"10.1021/acs.joc.4c00326\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Advanced analogs of piperidine and smaller homologues of tropane─3-substituted 6-azabicyclo[3.1.1]heptanes─were synthesized on a large scale using readily available bulk reagents. The key step of the approach involved the double alkylation reaction of malonate with <i>cis</i>-2,4-bis(mesyloxymethyl)azetidine-1-carboxylate, in turn easily prepared on up to 1 kg scale. After hydrolysis, <i>N</i>-Boc-6-azabicyclo[3.1.1]heptane-3,3-dicarboxylic acid was obtained (up to 400 g in a single run), which was used as a common intermediate for the preparation of all the title building blocks. In particular, Pb(OAc)<sub>4</sub>-mediated oxidative decarboxylation of this intermediate gave 2,6-methanopiperidone derivative (up to 400 g scale), while monodecarboxylation gave <i>N</i>-Boc-6-azabicyclo[3.1.1]heptane-3-carboxylic acids as an easily separatable mixture of <i>cis</i> and <i>trans</i> diastereomers (up to 100 g scale). Further functional group transformations gave diastereopure <i>cis</i>- and <i>trans</i>-<i>N</i>-Boc-monoprotected diamines and amino alcohols. Molecular structure analysis using exit vector parameters (EVP) revealed that <i>cis</i> isomers of 3-substituted 6-azabicyclo[3.1.1]heptanes are three-dimensional analogs of common 1,4-disubstituted piperidine <i>chair</i> conformer, whereas <i>trans</i> isomers can be considered as unusual \\\"<i>boat</i>\\\" piperidines.</p>\",\"PeriodicalId\":57,\"journal\":{\"name\":\"The Journal of Organic Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2024-08-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Journal of Organic Chemistry\",\"FirstCategoryId\":\"1\",\"ListUrlMain\":\"https://doi.org/10.1021/acs.joc.4c00326\",\"RegionNum\":2,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/7/11 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, ORGANIC\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Organic Chemistry","FirstCategoryId":"1","ListUrlMain":"https://doi.org/10.1021/acs.joc.4c00326","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/11 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CHEMISTRY, ORGANIC","Score":null,"Total":0}
3-Substituted 6-Azabicyclo[3.1.1]heptanes: Nonclassical Piperidine Isosteres for Drug Discovery.
Advanced analogs of piperidine and smaller homologues of tropane─3-substituted 6-azabicyclo[3.1.1]heptanes─were synthesized on a large scale using readily available bulk reagents. The key step of the approach involved the double alkylation reaction of malonate with cis-2,4-bis(mesyloxymethyl)azetidine-1-carboxylate, in turn easily prepared on up to 1 kg scale. After hydrolysis, N-Boc-6-azabicyclo[3.1.1]heptane-3,3-dicarboxylic acid was obtained (up to 400 g in a single run), which was used as a common intermediate for the preparation of all the title building blocks. In particular, Pb(OAc)4-mediated oxidative decarboxylation of this intermediate gave 2,6-methanopiperidone derivative (up to 400 g scale), while monodecarboxylation gave N-Boc-6-azabicyclo[3.1.1]heptane-3-carboxylic acids as an easily separatable mixture of cis and trans diastereomers (up to 100 g scale). Further functional group transformations gave diastereopure cis- and trans-N-Boc-monoprotected diamines and amino alcohols. Molecular structure analysis using exit vector parameters (EVP) revealed that cis isomers of 3-substituted 6-azabicyclo[3.1.1]heptanes are three-dimensional analogs of common 1,4-disubstituted piperidine chair conformer, whereas trans isomers can be considered as unusual "boat" piperidines.
期刊介绍:
The Journal of Organic Chemistry welcomes original contributions of fundamental research in all branches of the theory and practice of organic chemistry. In selecting manuscripts for publication, the editors place emphasis on the quality and novelty of the work, as well as the breadth of interest to the organic chemistry community.