Xu Tao Group, Ocean University of China: the first total synthesis of penicillin A and its whole family

Author: Yu Haiyong recently, Xu Tao Group, School of medicine, Ocean University of China, made a great breakthrough in the synthesis of marine natural products, and realized the first full synthesis of penicillin A and its whole family molecules about the complex natural products from marine fungi The research results were published in Chemical Science (DOI: 10.1039 / c9sc05252f) under the title of "total synthesis of (‒) - penicillin A and the related contractors" This article was selected as the front inside cover for key promotion Penicillin a (PMA) is one of a series of complex natural products isolated from Penicillium purpurogenum G59 fungal strains from marine sources by Cui Chengbin, a researcher of the Academy of Military Medical Sciences, in 2014 As a secondary metabolite of marine fungi, PMA and its family analogues show that Excellent antitumor activity (in vivo / in vitro), however, the absolute configuration of the compounds can not be determined (source: Chemical Science) PMA shows multiple synthesis challenges: 1) the North fragment is a kind of deac-fruticine a containing indolino-diketopyrazine with adjacent all carbon chiral centers The synthesis of this structure often depends on two-step or two-step method In the strategy construction of IR catalysis, Xu Tao's research group, born in Haiyong, creatively adopted the classical meerwein eschenmoser Claisen rearrangement strategy In one step, this challenging fragment synthesis was realized, and the first non enantioselective methodology of this reaction was developed and applied to the total synthesis of complex molecules 2) The South fragment contains 6,5 spiro ring system, in which each carbon atom of 6-membered ring is connected with O atom, showing a very high oxidation state, which is very rare in natural products The key spirocyclic framework can be synthesized by one-step electrochemical oxidation and aromatization of L-lysine as the starting material, and then the stereoselective installation of C8 as the quaternary carbon chiral center can be completed by overcoming the steric resistance effect through the epoxy oriented 1,2 addition reaction first reported by the research group 3) Finally, the coupling of the north and South fragments met with unimaginable difficulties After three months of optimization, the author finally successfully realized the first asymmetric total synthesis of (- - penicillin a In this synthesis, the aggregation strategy is used to achieve efficient and integrated synthesis, and the total synthesis of four natural products including penicillin A is completed, of which the longest linear step (LLS) is 10 The first unit to complete this paper is the school of medicine of Ocean University of China Professor Xu Tao, the corresponding author, is the National Youth thousand talents program, the young experts of Taishan Scholars, the outstanding young scholars of Aoshan talents of ocean National Laboratory, and the three-level teaching candidates of Zhufeng of Ocean University of China The first author of this paper is the master of Medical College born in Haiyong and Zongyan This work was supported by NSFC youth, general and major projects (81973232, 81991522), NSFC Shandong joint fund key projects (u1706213, u1606403), etc Co first author Yu Haiyong (left) and Zongyan (right) front inside cover