63112-94-7Relevant academic research and scientific papers
Streamlined Total Synthesis of Uncialamycin and Its Application to the Synthesis of Designed Analogues for Biological Investigations
Nicolaou,Wang, Yanping,Lu, Min,Mandal, Debashis,Pattanayak, Manas R.,Yu, Ruocheng,Shah, Akshay A.,Chen, Jason S.,Zhang, Hongjun,Crawford, James J.,Pasunoori, Laxman,Poudel, Yam B.,Chowdari, Naidu S.,Pan, Chin,Nazeer, Ayesha,Gangwar, Sanjeev,Vite, Gregory,Pitsinos, Emmanuel N.
supporting information, p. 8235 - 8246 (2016/07/15)
From the enediyne class of antitumor antibiotics, uncialamycin is among the rarest and most potent, yet one of the structurally simpler, making it attractive for chemical synthesis and potential applications in biology and medicine. In this article we describe a streamlined and practical enantioselective total synthesis of uncialamycin that is amenable to the synthesis of novel analogues and renders the natural product readily available for biological and drug development studies. Starting from hydroxy- or methoxyisatin, the synthesis features a Noyori enantioselective reduction, a Yamaguchi acetylide-pyridinium coupling, a stereoselective acetylide-aldehyde cyclization, and a newly developed annulation reaction that allows efficient coupling of a cyanophthalide and a p-methoxy semiquinone aminal to forge the anthraquinone moiety of the molecule. Overall, the developed streamlined synthesis proceeds in 22 linear steps (14 chromatographic separations) and 11% overall yield. The developed synthetic strategies and technologies were applied to the synthesis of a series of designed uncialamycin analogues equipped with suitable functional groups for conjugation to antibodies and other delivery systems. Biological evaluation of a select number of these analogues led to the identification of compounds with low picomolar potencies against certain cancer cell lines. These compounds and others like them may serve as powerful payloads for the development of antibody drug conjugates (ADCs) intended for personalized targeted cancer therapy.
Aromatic Spiranes XXI [1]: Syntheses of Methyl Substituted Phthalaldehydic Acids and their Ethyl and Methyl Esters as Synthones for Syntheses of Methylated 2,2′-Spirobiindandiones
Neudeck
, p. 201 - 217 (2007/10/03)
The isomeric methyl phthalaldehydic acids 11 were obtained from phthalides 4 by bromation (NBS) to the 3-bromo derivatives 7 and subsequent hydrolysis with water. 4 in turn were accessible from dimethyl methyl benzoates 1 by dibromination with NBS and subsequent thermical cyclization to the bromo derivatives 3 which, on catalytic dehalogenation, afforded the phthalides 4. Reaction of 11 with methanol or ethanol gave the pseudo-esters 13 and 14, resp. Short treatment of 11 with diazomethane on the other hand yielded the methyl formyl benzoates 15b to 15e. Prolonged reaction (several hours) gave the oxiranyl compounds 17; in addition, the acetonyl derivatives 18 were also found, obviously formed by a double methylene insertion into 15. All reactions proceeded with good to excellent yields.
A Chiral Adamantanophane: Preparation, Enantiomer Separation, Theoretical and Experimental Circular Dichroism and Absolute Configuration
Grimme, Stefan,Lemmerz, Ralf,Voegtle, Fritz
, p. 2081 - 2088 (2007/10/02)
Exchange of aromatic units (e.g. benzene) for aliphatic/alicyclic building blocks (e.g. adamantane) in cyclophanes leads to molecules of the "araliphane" type.The synthesis of the highly strained (1,3)adamantanometacyclophanes 5a-c is described.The cyclophane skeletons of these molecules are conformationally rigid and therefore 5a-c are planar-chiral.The circular dichroism of 5c has been calculated theoretically with NDDO/MRD-CI methods and was measured.Agreement of theory and experiment is good, a comparison of both allows the assignment of the absolute configuration of the two enantiomers of 5c with high probability.Furthermore, analysis of the n?* band in the CD spectrum yields a simple general rule to determine the conformation of the carboxyl group in phenyl ester substructures.Theoretical calculations of the strain energy (Es) of 5c reveal the distribution of strain within the molecule. - Key Words: Adamantanophanes / Calculations, CI / Circular dichroism / Cyclophanes / Strain energy
