- Constructing Saturated Guanidinum Heterocycles by Cycloaddition of N-Amidinyliminium Ions with Indoles
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We report that structurally complex guanidinium heterocycles can be prepared in one step by regio- and stereoselective [4 + 2]-cycloadditions of N-amidinyliminium ions with indoles or benzothiophene. In contrast to reactions of these heterodienes with alkenes, density functional theory (DFT) calculations show that these cycloadditions take place in a concerted asynchronous fashion. The [4 + 2]-cycloaddition of N-amidinyliminium ions (1,3-diaza-1,3-dienes) with indoles and benzothiophene are distinctive, as related [4 + 2]-cycloadditions of N-acyliminium ions (1-oxa-3-aza-1,3-dienes) are apparently unknown.
- Allred, Tyler K.,Shaghafi, Michael B.,Chen, Pan-Pan,Tran, Quan,Houk,Overman, Larry E.
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supporting information
p. 7618 - 7623
(2021/10/12)
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- The insulin secretory action of novel polycyclic guanidines: Discovery through open innovation phenotypic screening, and exploration of structure-activity relationships
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We report the discovery of the glucose-dependent insulin secretogogue activity of a novel class of polycyclic guanidines through phenotypic screening as part of the Lilly Open Innovation Drug Discovery platform. Three compounds from the University of California, Irvine, 1-3, having the 3- arylhexahydropyrrolo[1,2-c]pyrimidin-1-amine scaffold acted as insulin secretagogues under high, but not low, glucose conditions. Exploration of the structure-activity relationship around the scaffold demonstrated the key role of the guanidine moiety, as well as the importance of two lipophilic regions, and led to the identification of 9h, which stimulated insulin secretion in isolated rat pancreatic islets in a glucose-dependent manner.
- Shaghafi, Michael B.,Barrett, David G.,Willard, Francis S.,Overman, Larry E.
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p. 1031 - 1036
(2014/03/21)
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