Angelw: the team of Alois f ü rstner in Germany completed the total synthesis of belizentrin methyl ester

Belizentrin (1, scheme 1) was obtained in 2013 from Prorocentrum belizeanum culture of benthic dinoflagellate by valdiglesias et al With low isolation rate (Mar drugs, 2013, 11, 4328) In vitro, belizentrin has the effect of destroying the neural network of cerebellar cell culture The instability of belizentrin (1) makes its structural analysis very challenging Based on spectral analysis, computational studies and comparison of literature data, the author proposed a three-dimensional structure as shown in scheme 1, and determined the relative configuration of large ring and side chain, but the relationship between these structures is not clear Belizentrin (1) has a unique chemical structure: a 25 membered ring containing both lactone and amide bonds; the Tetraene substructure of the lower sector is cut off by the methylene outside the ring, and the conjugation of two distal olefins and esters will produce considerable enthalpy gain, leading to the instability of the structure; at the same time, the scattered double bond arrangement makes the large ring skeleton rigid; belizentrin There are 16 chiral centers, 11 of which exist in the side chain with high hydrophilicity with 6 secondary hydroxyl and 2 ether rings, and 4 of the other 5 centers gather in the third-order hemiacetal structure Recently, Alois f ü rstner research group of German Max Planck Coal Research Institute reported the total synthesis of belizentrin methyl ester (2) (DOI: 10.1002 / anie 201805125) on angew Chem Int ed (source: angew Chem Int ed.) the instability of scheme 1: 1 makes the synthesis of 1 or 2 difficult Therefore, the author takes its methyl 2 as the synthesis target in order to improve the stability of the compound without affecting its biological activity Because the stereochemical correlation between the side chain and the macrocycle has not been determined, the c17-c18 double bond has become an obvious construction site, which requires E-selective olefinization and is compatible with other functional groups in the molecule Based on the previous research experience, the author thinks that Julia kocienski method is more suitable for olefinization, and macrolide is prior to macrolide The intramolecular ammonolysis of lactone precursor initiated by amide bond is a very rare macrocyclization strategy The required precursor can be assembled by cross coupling reaction of synthetic block C, D and e to minimize the synthesis steps Considering the symmetry, the tetrahydropyran part of polyhydroxy fragment a can be traced back to D-glucose, while the trans-2,5-disubstituted tetrahydrofuran ring h can be obtained from I through a series of transformations The CIS triol moiety connecting the two ether rings can be constructed by stereoselective olefinization of F and H fragments and catalyst controlled dihydroxylation Specific synthesis route: firstly, we synthesized trans-2,5-disubstituted tetrahydrofuran ring 5 (scheme 2) from L-glutamic acid (3) The key step is fluorine promoted Michael addition, and the resulting compound 5 is the only isomer The conversion of the ester end to the required tetrazolyl sulfone is smooth, as is the conversion of triphenylmethyl ether to the unstable aldehyde 9 (source: angelw Chem Int ed.) the synthesis of Julia reagent 21 (scheme 3): firstly, the reaction is converted from glucopyranosyl 10 to C-glycoside 11 by three known reactions, and alcohol 12 is obtained by removing TBS protecting group After Swern oxidation, enol ether 13 is obtained by Wittig olefinization with [meoch = PPH 3] A large amount of methyl ester 14 can be obtained by PCC treatment 13 After that, KMnO 4 was used to oxidize the terminal alkene to corresponding hydroxyketone 15 However, only trace amounts of 15 are converted to stable compounds 18 α - bromoketone 16 is easy to debrominate, so the substrate is easy to degrade during the conversion of 16 to phosphonium salt 17 Considering that ET 3N is particularly effective in N-alkylation of frozen benzene, the author used 16 to carry out p-alkylation of PPH 3 in order to achieve the same effect Finally, 17 was obtained in almost quantitative yield in solid benzene After alcoholization of carbonyl alkene, the corresponding alkene ketone (E / z = 18:1) was obtained by reaction with aldehyde 9 In order to clarify that the main product is e-isomer, the author first reduced ketone by CBS, and then used (dhqd) 2 aqn (23) as a ligand to carry out Sharpless dihydroxylation of allyl alcohol 19, and obtained triol 20 with good yield and selectivity Compared with other non enantiomers with clear configuration (prepared by two independent routes), the formation of ring derivatives was detected by NMR and determined by Mosher ester analysis Finally, 20 was protected by tes to obtain the structure fragment 21 of the tail region of belizentrin methyl ester (2) (source: angew Chem Int ed.) synthesis of coupling reaction substrate 34 (scheme 4): the author took 4-pentenoic acid (24) as raw material, and obtained diene 27 through esterification, cross decomposition and enol silylation Under the catalysis of chromium, the adduct 30 (95%, EE) was obtained by asymmetric hetero Diels / alder reaction with aldehyde 29 Then, enone 31 was oxidized by the improved Saegusa, and the reaction between enone 31 and memgcl resulted in a single enantiomeric tertiary alcohol 32 Then, the spontaneous closed-loop of butyrolactone was realized by asymmetric dihydroxylation 33% of the two hydroxyl groups were protected by TES The product 33 was treated with pH 3 PBR 2 to exchange the functional groups of primary methyl ether to obtain bromide 34, which can be used as a pre nucleophilic reagent for fragment coupling (source: angew Chem Int ed.) synthesis of another substrate 38 (scheme 5): the author uses propargyne as raw material, silanizes it to form organic copper reagent 36, quenches it with 39 in the presence of BF 3oet 2 to get alcohol 37, and then esterifies it with acrylic acid 40 to get ester 38 by the method reported by Yamaguchi (source: angelw Chem Int ed.) the synthesis of triethylene iodide 47 (scheme 6): the author carried out the regioselective silylation of 2-butyne-1-ol (41), and converted the terminal hydroxyl group into the corresponding allylic bromide 43, then reacted with Knoevenagel by alkylation to obtain allylic ester 44, and then converted it into allylic acetate 45 The intermediate 46 was obtained by allyl Suzuki reaction of the compound with borate derivative 49, and then treated with tipsotf / 2,6-lutidine Finally, allyl iodide 47 was obtained by iodine demethylsilyl reaction (source: angelw Chem Int ed.) fragment assembly and 2 total synthesis (scheme 7): firstly, 38 and 47 were still coupled to get 50, and alkenylsilane was selectively iodized with [py 2I] BF 4, and the resulting compound 51 was Negishi coupled with highly functional organic zinc derivative 52 to get 53 In the separation of free amine 54, a large amount of loss is caused by the partial oligomerization of the concentrated mixture When the crude amine 54 is heated in the dilute toluene solution, the lactam 55 can be obtained, and the reaction can be accelerated by adding excessive 2-pyridone into the reaction solution After enough large ring segments 55 were obtained, the end PMB ether was broken by triphenyl tetrafluoroborate The steric hindrance is caused by the protection of all the tertiary isomers, which makes the coupling of fragments very difficult The olefinization of kocienski must be carried out with α - acylated aldehydes containing free hydroxyls, and the top of the group is easy to form hemiacetals or hydrates In addition, this kind of polyunsaturated compound is also very sensitive to medium alkaline conditions Inspired by the literature, the author tried to weaken the basicity of nucleophiles derived from 21, and the conversion of lithium sulfone to CeCl3 was greatly improved by ketene enolization Through a large number of experiments, the author found that ZnCl2 / LiHMDS combination was more effective in DMF / DMPU mixed solvent, and the yield of e-57 was 25-30% Then, the author deprotected all the eight silyl ethers in the product 57 to get the expected product 2 (source: angel Chem Int ed.) the 13C NMR spectrum of belizentrin methyl ester (2) shows a systematic drift (about - 0.4ppm) compared with the data of belizentrin (1) reported in the literature; after the systematic difference is corrected, almost all chemical shifts are well matched (C7, C9, C23 Except), especially considering that the natural product is carboxylic acid, while the synthetic sample is methyl ester Similarly, 1H NMR data, including noe / ROESY correlation, are completely consistent with the report Therefore, the author tends to think that the structure of 1 correctly describes the chemical composition and relative stereochemistry of belizentrin; however, the exact configuration can only be determined after other possible non enantiomers are synthesized and the end methyl ester is hydrolyzed to free acid Conclusion: Alois f ü rstner group completed the synthesis of belizentrin methyl ester, a natural marine product The synthesis highlights include: the construction of the third-order hemiacetal substructure by asymmetric oxo-diels / alder reaction; the connection of two synthetic blocks by Negishi cross coupling and the macrocyclization strategy based on the intramolecular ammonolysis of spironolactone; the connection between the side chain of polyols and the macrocyclic parent nucleus by the improved kocienski olefinization Professor Alois f ü rstner's research direction: Total Synthesis of natural products; research on synthesis methods, especially metal catalyzed decomposition of alkynes.