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    Home > The Nelson group of UCLA completed the synthesis of (±) - vibralactone

    The Nelson group of UCLA completed the synthesis of (±) - vibralactone

    • Last Update: 2018-12-28
    • Source: Internet
    • Author: User
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    Vibralactone (1) is a terpenoid natural product first isolated from the basidiomycete fungus boreosterium vibrans by Professor Liu Jikai of Kunming Institute of Botany, Chinese Academy of Sciences in 2006 It is not only an inhibitor of pancreatic lipase (IC50 = 0.4 μ g / ml), but also an inhibitor of casein white hydrolytic peptidase CLPP Due to its unique β - lactone fused double ring structure and remarkable biological activity, it has attracted the attention of synthetic chemistry and chemical biology in recent years In 2008, Snider group completed the first full synthesis of (±) - vibralactone with ten steps (total yield of 9%), including six redox operations and a complex scheme 1A; in 2016, brown group completed (±) - vibralactone with eleven steps (total yield of 16%) Four redox operations and a scheme 1B are included in the synthesis Recently, the team of Professor Hosea M Nelson at UCLA has realized (±) - vibralactone (1) total synthesis (scheme 1c) by five steps reaction The synthesis process has high atomic economy, no protective base operation, and only one oxidation-reduction operation The results were published online at angew Chem Int ed (DOI: 10.1002 / anie 201812711) (picture source: angew Chem Int ed.) (±) - vibralactone (1) inverse synthesis analysis is shown in scheme 2 It is assumed that the core skeleton of (±) - vibralactone (1) can be obtained from intermediate 3 by ring expansion and reduction strategy, and then the highly strained tricyclic ester 3 can be constructed by cyclopropylation of Dewar isomer of isoprene pyranone 2 It is important that the photochemical valence bond isomerization of pyranone 2 can introduce the crowded β - lactone and the quaternary carbon chiral center to construct the basic framework of the target molecule (picture source: angelw Chem Int ed.) firstly, the author irradiated isoprene pyranone 2 with 300 nm light source for valence bond isomerization, and obtained oxyheterobicyclo [2.2.0] hexenone 4 (scheme 3) in 83% yield Next, the cyclopropanization of bicyclic Intermediate 4 was studied, and cyclopropane 3 was obtained under the catalysis of RH 2 (ESP) 2 Its structure was confirmed by X-ray crystallography (photo source: angelw Chem Int ed.) bishop research group once reported the method of conversion of dicyclic [2.1.0] pentane skeleton to cyclopentene via transition metal catalysis Therefore, the author attempts to add the C-C bond of 3 strain to the metal oxidation under the catalysis of transition metal to obtain the metal ring compound 6, so as to realize the cyclopentenyl ester 5 (scheme 4a) generated by the ring expansion of cycloalkane 3 Bishop team found that the success of the transformation depends on the CIS relationship between β - H and metal center in the similar structure of 6, and the oxidation addition of substrate 3 may cause the metal center and β - h to be in trans form It is not surprising that no ring expanding products have been obtained in the presence of various transition metal complexes Then, the author found that the α - H deprotonation of the exocyclic ester can produce the enolase 8, in which the bridging C-C bond can produce the allylic anion 9 through the E1cb - type fracture; 9 can get the enolase 5 through the deprotonation, thus the scheme 4b of the natural product can be constructed in four steps Finally, under mild alkaline condition (DBU), the author realized the ring expansion of 3 and obtained the key intermediate 5 (scheme 4C) (image source: angelw Chem Int ed.) in the previous (±) - vibralactone synthesis route, due to the instability of β - lactone, it needs multiple protective groups and redox operations before its introduction In this paper, we attempt to selectively reduce the esters with less steric hindrance by kinetic control, and realize the reduction of ethyl ester by dibal-h, and finally get (±) - vibralactone (scheme 5) (picture source: angel Chem Int ed.) conclusion: Professor Hosea M Nelson's research group started from the known isoprene pyranone 2, and completed the synthesis of (±) - vibralactone in a total yield of 4.3% after four steps of reaction (five steps based on the commercially available raw materials) The highlights of the synthesis are: the process has atomic economy, no need to protect the group, only one oxidation-reduction operation; through the key photochemical valence bond isomerization, the quaternary carbon chiral center and β - lactone part are introduced, and then the carbon ring parent nucleus is constructed through cyclopropanization and ring expansion strategy The synthetic pathway developed by the authors will be helpful to further explore the biological activity and structure-activity relationship of (±) - vibralactone.
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