Total Synthesis of Daphniphyllum Alkaloids: From Bicycles to Diversified Caged Structures

Guo, Lian-Dong1,2,3,4; Chen, Yuye1,2,3,4; Xu, Jing1,2,3,4

2020-11-17

10.1021/acs.accounts.0c00532

ACCOUNTS OF CHEMICAL RESEARCH   影响因子和分区

0001-4842

1520-4898

["CONSPECTUS: Native to the Asia-Pacific region and widely applied in traditional Chinese medicine, the genus Daphniphyllum has produced over 330 known Daphniphyllum alkaloids. Investigations into these alkaloids have shown an exceptional range of interesting bioactivities. Challenging and caged polycyclic architectures and the promising biological profiles make Daphniphyllum alkaloids intriguing synthetic targets. Based on their backbones, these alkaloids can be categorized into 13-35 structurally distinct subfamilies. In addition to our work, almost 30 impressive total syntheses of Daphniphyllum alkaloids from seven subfamilies, namely, daphniphylline-type, secodaphniphylline-type, daphnilactone A-type, bukittinggine-type, daphmanidin A-type, calyciphylline A-type, and calyciphylline B-type alkaloids, have been reported by 11 research groups. However, many Daphniphyllum alkaloid subfamilies remain inaccessible by chemical synthesis.","In this Account, we summarize our recent endeavors in the total synthesis of Daphniphyllum alkaloids commencing from simple chiral bicyclic synthons. Daphniphyllum alkaloids with diversified skeletons from four different subfamilies, namely, calyciphylline A-type, daphnezomine A-type, bukittinggine-type, and yuzurimine-type alkaloids, have been achieved. Furthermore, the tricyclic core structure of daphniglaucin C-type alkaloids daphnimacropodines was also synthesized. First, we describe a 14-step synthesis of calyciphylline A-type alkaloid (-)-himalensine A, which features a mild Cu-mediated nitrile hydration, an intramolecular Heck reaction to assemble the pivotal 2-azabicyclo[3.3.1]nonane moiety, and a Meinwald rearrangement to introduce the critical oxidative state into the skeleton. We then introduce the synthesis of daphnezomine A-type alkaloid dapholdhamine B, which possesses a unique aza-adamantane core. This target molecule was fabricated using key reactions including Huang's amide-activation-annulation. An unexpected radical detosylation during the synthesis of dapholdhamine B further inspired an ambitious radical cyclization cascade strategy, which eventually led to an efficient total synthesis of bukittinggine-type alkaloid (-)-caldaphnidine O. This highly chemo-, regio-, and stereoselective radical reaction cascade also shed light on the synthetic strategy of other alkaloids with caged structures. We next describe the first total synthesis of yuzurimine-type alkaloid (+)-caldaphnidine J. The key steps in our approach include a Pd-catalyzed regioselective hydroformylation and a novel Swern oxidation/ketene dithioacetal Prins reaction cascade. The work has achieved the first synthesis of a member of the largest subfamily of Daphniphyllum alkaloids. Finally, we show our efforts toward the total synthesis of daphniglaucin C-type alkaloids. Overall, we hope that the interesting strategies and synthetic methods demonstrated in our efforts could inspire a wide variety of additional applications to natural product synthesis."]

SCI

英语

第一 ; 通讯

Shenzhen Science and Technology Innovation Committee["JCYJ20170817110515599","KQTD20150717103157174"] ; NSFC[21772082,21971104] ; Guangdong Innovative Program[2019BT02Y335] ; Guangdong Provincial Key Laboratory of Catalysis[2020B121201002] ; Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis[ZDSYS20190902093215877]

Chemistry

Chemistry, Multidisciplinary

WOS:000592834600022

AMER CHEMICAL SOC

CHEMISTRY

Web of Science

1.Southern Univ Sci & Technol, Dept Chem, Shenzhen 518055, Peoples R China
2.Southern Univ Sci & Technol, Shenzhen Grubbs Inst, Shenzhen 518055, Peoples R China
3.Southern Univ Sci & Technol, Guangdong Prov Key Lab Catalysis, Shenzhen 518055, Peoples R China
4.Southern Univ Sci & Technol, Shenzhen Key Lab Small Mol Drug Discovery & Synth, Shenzhen 518055, Peoples R China

Guo, Lian-Dong,Chen, Yuye,Xu, Jing. Total Synthesis of Daphniphyllum Alkaloids: From Bicycles to Diversified Caged Structures[J]. ACCOUNTS OF CHEMICAL RESEARCH,2020,53(11).

Guo, Lian-Dong,Chen, Yuye,&Xu, Jing.(2020).Total Synthesis of Daphniphyllum Alkaloids: From Bicycles to Diversified Caged Structures.ACCOUNTS OF CHEMICAL RESEARCH,53(11).

Guo, Lian-Dong,et al."Total Synthesis of Daphniphyllum Alkaloids: From Bicycles to Diversified Caged Structures".ACCOUNTS OF CHEMICAL RESEARCH 53.11(2020).