Angelw: the rycnovsky group of the University of California completed the asymmetric synthesis of (- - himeradine a

(-) - himeradine a (1) is a kind of lycopodine alkaloid (Figure 1) isolated by Kobayashi research group in 2003 It has cytotoxic effect on mouse lymphoma L1210 cells In vitro IC 50 is 10 μ g / ml The structure of 1 is characterized by 7 rings, 10 chiral centers, quinozolinyl groups and three nitrogen atoms connected by methylene and cage like pentacyclic parent nucleus Lycopodine alkaloids (such as huperizine A and palhinine a) have unique chemical structures and interesting biological activities, which have become the research target of synthetic chemists Carter Group completed the synthesis of quinazoline fragments through 18 longest linear steps (LLS); so far, only the shair group reported the total synthesis of (- - himeradine a (33 LLS) Recently, Scott D rychnovsky group of University of California, Irvine completed the asymmetric synthesis of (- - himeradine a through the key cross ring Mannich reaction and rapid construction of quinazoline ring through 17 longest linear steps, which was recently published in angel Chem Int ed (DOI: 10.1002 / anie 201910129) (photo source: angelw Chem Int ed.) inverse synthesis analysis of (-) - himeradine a (Figure 2): the synthesis method of (-) - himeradine A is derived from the total synthesis of fastigiine developed by the author in the early stage: inspired by its biosynthesis, fastigine mother nucleus can be assembled by the intermediate 3 through the trans ring Mannich reaction, and at the same time, quinozoline ring can be constructed In the total synthesis of fastigiine, Mannich precursor was assembled by B-alkyl Suzuki coupling and 1,4-addition of decarboxylation radicals in the later stage In order to use this method in the synthesis of himeradine a, the author envisages that piperidine unit 5 is coupled with bromobenzophenone 4, which is the key intermediate in the synthesis of fastigiine a The allylamine configuration in piperidine 5 was constructed by catalyst controlled Overman rearrangement; the enantiomeric pure dialkypiperidine 6 could be synthesized by two steps of commercial 2-bromo-4-methylpyridine (7) (picture source: angel Chem Int ed.) specific synthesis route: firstly, the author used bromopyridine 7 and 3-butyne-1-ol as starting materials, and constructed racepipidine 6 (scheme 1) containing quinozoline ring by Sonogashira coupling and Rh / Al 2O 3-h 2 asymmetric hydrogenation (picture source: angelw Chem Int ed.) after obtaining a large number of racemic piperidine 6, the author investigated the resolution effect of various chiral acids (Table 1) At last, the author found that the best resolution (41% yield, 95% ee) was obtained by using 1 equivalent dibenzoyl-d-tartaric acid in methanol In addition, the absolute configuration of piperidine 6 was confirmed by the single crystal structure of dibenzoyl-d-tartrate 9 (image source: angel Chem Int ed.) later, the author obtained piperidine 11 (scheme 1) by protecting (-) - 6 (salt 9), and then obtained olefin 12 (> 20:1) by asymmetric allylation Scheme 2: olefin 12 was decomposed with crotonaldehyde to produce olefin aldehyde as a single isomer, which was reduced to alcohol 14 by NaBH 4; after it was converted to trichlorimine ester, trichloroacetamide 15 was obtained by treating with palladium catalyst (-) - cop Cl, and then piperidine 5 was obtained by protecting group After two fragments of piperidine 5 and bromobenzophenone 4 were obtained, they were coupled with B-alkyl Suzuki to obtain enone 16, and then stereoselective 1,4-addition with glycine protected by N-Boc under iridium catalyst / Blue led to produce non enantiomer 17 / 18, which can be separated after deprotection Subsequently, the author selectively protected the primary alcohol of β - isomer 18, and then oxidized the secondary alcohol to diketone 19 In o-DCB at 165 ℃, diketone 19 was treated with excess CSA to remove all BOC protecting groups and form imines, and then the key c14-c6 bond and C14 position chiral center were constructed by spontaneous trans ring Mannich reaction When the crude product is neutralized by ET 3N, it is N-alkylated with C2 '- OTS to form quinazoline ring Finally, the author selectively acetylated pyrrolidine nitrogen to (- - himeradine a It is worth noting that the author finally separated himeradine a in the form of ditrifluoroacetate, which is more stable and helpful for spectral analysis (photo source: angelw Chem Int ed.) the 1H and 13C NMR of (-) - himeradine A and HRMS are completely consistent with the data reported by hair, but there are differences between the 1H and 13C NMR of (-) - himeradine a from natural sources Small chemical shift differences are often observed in the salts of alkali alkaloids, which may depend on the amount of TFA in the sample The optical rotation of natural products, shair synthetic samples and the author's synthetic samples are basically the same, which supports the structure of (- - himeradine a Conclusion: Scott D rycnovsky's group completed the asymmetric synthesis of himeradine a by using 17 longest linear steps The synthesis features include asymmetric piperidine hydrogenation, classic salt forming resolution, asymmetric Overman rearrangement, B-alkyl Suzuki coupling, and the bionic trans ring Mannich cascade reaction of 5 bonds and 4 rings constructed by "one pot" method.