Angelw: team of daimingji, Purdue University, USA completed the total synthesis of 100 alkaloids containing oxyspironolactone

Many bioactive natural products, especially alkaloids, are contained in the plants of stemonaceae So far, more than 150 alkaloids have been isolated, most of them have the characteristic parent nucleus of pyrrole [1,2-a] nitrogen heterocycle Many members of the stemonamide group contain heterospironolactone (Figure 1a), such as bisdehydrone (1a), (ISO), bisdehydrostemonine (1b and 1c), stemonines A and B (1D and 1E), tuberstemoamide (1F), sessilifoliamide a (1g), (dihydro) stemonine（ 1H and 1I) and stemonenone (1J) Among the above compounds, aromatic pyrrole ring was found in 1a - 1D, while pyrrolidine (1H and 1I) or its oxidized derivatives (1F, 1g, 1J and 1K) were found in 1F - 1K Moreover, 1b, 1C, 1D and 1E all contain γ - butyrolactone in the C3 position of pyrrole ring, which makes the stereocenter of C18 unstable and prone to differential isomerization All of the above structural features greatly increase the complexity of the structure and the difficulty of total synthesis of these compounds In 2003, Williams and his colleagues completed the full synthesis of stemonine (1m) for the first time; in 2017, Chida, Sato and their colleagues developed a general route to synthesize both stemonine (1m) and saxorum (1n) by stemomide (1L) However, the total synthesis of 100 alkaloids (1a - 1K) containing oxaspironolactone has not been reported The introduction of acid sensitive oxy heterospironolactone and the stereochemical control of the center of the spiro ring (C11) all pose a great challenge to its total synthesis (photo source: angelw Chem Int ed.) recently, a palladium catalyzed oxidative carbonylation of hydroxycyclopropanol to one-step synthesis of oxyspironolactone (scheme 1a) was reported by daimingji research group of Purdue University in the United States The scheme 1A was used for the first full synthesis of bisdehydronostemonine and bisdehydrostemonine（ DOI: 10.1002/anie.201809114 ） 。 The synthesis strategy of bisdehydrone and bisdehydrosonine is shown in scheme 1b Palladium catalyzed oxidative carbonylation of intermediate 8 to oxaspironolactone 9, which can be used as a key intermediate in the synthesis of Stemona alkaloids Cyclopropanol 8 can be obtained from tricyclolactone 7 by α - ethylation and kulinkovich reaction, while 7 can be synthesized from allyl alcohol 6 by palladium catalyzed oxidative cyclization and carbonylation internal esterification in series In addition, a new method has been developed to convert pyrrole into pyrrolidine or γ - butyrolactam This method can be used to obtain the corresponding natural product (1F - 1I) without pyrrole by bisdehyrone eostemonine (1a) (image source: angelw Chem Int ed.) the specific synthesis route is shown in scheme 2 First of all, the commercial raw materials 10 and 11 were converted into pyrrole 12 through the improved Clauson Kaas reaction and Weinreb amide formation reaction, and the enone obtained from nucleophilic addition of vinyl Grignard reagent was reduced to allyl alcohol 6 by NaBH 4 Then, the author tried to transform 6 into tricyclic lactone 7 by oxidative carbonylation, but no target product 7 was obtained Therefore, the indirect method was used to obtain α, β - unsaturated ester 13 from 6 and methyl acrylate through olefin metathesis Then, the azacycloheptene ring and fused γ - butyrolactone ring were constructed through Friedel crafts cyclization and internal esterification series reaction catalyzed by boron trifluoride ether, and tricyclone 7 was successfully obtained Then the author used LDA / ETI to carry out α - ethylation of 7 to obtain 14:15 (1.3:1) mixture, and 14 was epiisomerized to target product 15 under the condition of K 2CO 3 / MeOH The relative stereochemistry of 7 and 14 was confirmed by X-ray crystallography After getting tricyclic lactone 15, the author tried to use kulinkovich reaction to convert it into Cyclopropanol 8, and explored the standard and improved kulinkovich reaction conditions successively, but the yield could not meet the requirements The author also tried to introduce oxy heterospironolactone containing external methylene by dreing Schmidt reaction of lactone 15 and 2 - (bromomethyl) methyl acrylate, which was not successful Then, according to the kulinkovich method reported by Corey, using clti (OiPr) 3 instead of common Ti (OiPr) 4, the author obtained Cyclopropanol 8 in 63% yield The product 9a and its stereoisomer mixture (2.3:1) were obtained under the catalysis of waymouth catalyst [PD (neoc) (OAC)] 2 (OTF) 2 The isomer can be isomerized to 9A under TFA / CH2Cl2 After obtaining oxaspironolactone 9a, the author introduced α - outer methylene according to the method reported by eschenmosers, and obtained compound 17; then isomerized the outer methylene into inner ring double bond under Ru 3 (CO) 12 catalysis, and completed the full synthesis of bisdehydroneostemonine (1a) for the first time, its structure was confirmed by X-ray crystallography Although 1b-1c and 1d-1e are both differential isomers in nature, the C11 differential isomer of 1A has not been reported yet Because the C11 epimer of 9A was obtained during the formation of oxaspironolactone, we hope to synthesize the C11 epimer of 1a by the same eschenmosers method and double bond isomerization method (image source: angelw Chem Int ed.) next, the author tried to introduce γ - butyrolactone at C3, and then convert bisdehyrone eostemonine (1a) into bisdehyrone (1b) However, there are many challenges in this process: firstly, the oxy heterospironolactone of bisdehydroneostemonine (1a) is sensitive to acid, and the subsequent reaction must be carried out under mild conditions; secondly, the two chiral centers of γ - butyrolactone are far away from the rest, so it is difficult to control the formation of new stereocenters by using the existing stereocenters; thirdly, C18 is introduced After stereocenter, the product is easy to be isomerized In view of the above problems, the author first introduced aldehyde group into C13 site of 1a to obtain product 18 by the improved Vilsmeier Haack reaction, and then 1,2-added with enol zinc derived from 19 to obtain the mixture of enantiomers 20 and 22 (1:1), which can be separated by column chromatography Subsequently, the author decided to use 20 for the total synthesis of bisdehydrosonine (1b) and 22 for the synthesis of bisdehydrosonine analogues Under the condition of t-BuOH / K 2CO 3, 21 was successfully obtained, and its C18 stereocenter was unstable, and it was easy to isomerize It has been found that in the mixed solvent of benzene and pyridine (1:1), the external methylene can be reduced smoothly, and bisdehydrosonine (1b) can be obtained in 86% yield and 9:1 non enantioselectivity According to the same scheme, 22 is transformed into bisdehydrosonine analogue 24 Conclusion: the team of Dai Mingji, Purdue University, USA, has completed the synthesis of racemates of 100 alkaloids bisdehydrone eostemonine (1a) and bisdehydrosteronine (1b) for the first time The key to its synthesis is to construct the oxy heterospironolactone by palladium catalyzed oxidative carbonylation, and to construct the 5-7-5 tricyclic parent nucleus of the target molecule by Lewis acid catalyzed Friedel crafts cyclization and internal esterification.