JACS: ingenious construction of natural product salimabromide

Salimabromide (scheme 1a, 1) is a kind of polyketone compound with antibacterial activity isolated from myxobacteria Its dense functional group structure and rigid four ring skeleton are unprecedented in natural products Salimabromide molecule contains four consecutive chiral centers, one of which is chiral quaternary carbon; in addition, the ring skeleton of tetrahydronaphthalene bromide is bridged with multi substituted seven membered carbon ring These structural characteristics make it difficult to synthesize Recently, Thomas magauer team from Innsbruck University in Austria reported the first total synthesis of salimabromide The highlight of this paper is that the author used acid catalyzed Wagner meerwein rearrangement / Friedel crafts cyclization to form tetrahydronaphthalene ring containing two adjacent quaternary carbon, and used the [2 + 2] cycloaddition of enoketimine intermediate and subsequent Baeyer Villiger oxidation to selectively construct cyclopentalactone containing three stereocenters (source: J am Chem SOC.) the author conducted inverse synthesis analysis (scheme 1b) on salimabromid (1) There are four consecutive chiral centers in target molecule 1 First, the C12 quaternary carbon centers are constructed Then, three consecutive carbon stereocenters, C11, C13 and C15, can be constructed by one-step reaction Therefore, 1 can be simplified to 5 Intermediate 5 can be constructed by intramolecular [2 + 2] cycloaddition of enoleimine ions derived from 6 Intermediate 6 can be synthesized from simple substrate 7 by acid catalyzed Wagner meerwein rearrangement / Friedel crafts cyclization (source: J am Chem SOC.) the author first synthesized the intermediate 12 (scheme 2) Starting from commercial raw materials 8 and 9, intermediate 10 was obtained by Claisen Schmidt condensation The intermediate 11 is obtained by the next step of heterogeneous catalytic hydrogenation Through the standard Corey chaykovsky reaction, the epoxy intermediate 7 was formed Then, the first key step was explored: acid catalyzed Wagner meerwein rearrangement / Friedel crafts cyclization The author found that 7 under the condition of n-hexane / sulfuric acid or dichloromethane / titanium chloride (IV), the product 12 with 30% yield and the by-product 13 with 10% yield can be obtained The results show that the selectivity can be increased to 12:13 = 8:1 with strong hydrogen bond donor and weak affinity HFIP as reaction solvent At the same time, the rearrangement reaction of enantiomeric enrichment substrate 7 was studied, which laid a foundation for the subsequent asymmetric synthesis of 1 (source: J am Chem SOC.) after obtaining the key intermediate 12, the author began to study the total synthesis of salimabromid (1) After hydroxyl protection and DDQ dehydrogenation, 14 Then 14 demethylated and upper trifluoromethylsulfonate were converted into intermediate 15 The intermediate 16 can be obtained by Negishi coupling with ethyl and then removing the hydroxyl group Then 16 was oxidized, Wittig allylated and aminated to obtain intermediate 6 Next, the author explored the cycloaddition procedure of ketenimine ion [2 + 2] After optimization, the key intermediate 5 (yield 89%, 1.9 g) was obtained in high yield After the successful introduction of all the three-dimensional carbon centers, the problems still need to be solved are the oxidation of the quaternary carbon ring and the bromination of the benzene ring In this paper, selenium dioxide was used to oxidize intermediate 5, and a few raw materials were converted into allyl alcohol 22 The yield could not be increased by prolonging the reaction time After five cycles, 250 mg intermediate 22 was obtained Then 22 reacted with copper acetate / oxygen to obtain 23 and 24 (23:24 = 1:3.2) 23 and 24 can be separated by column The final step is to introduce bromine on 24 The author has tried many conditions and found that under the condition of trifluoroacetic acid / silver trifluoroacetate / bromine, the natural product 1 with a yield of 50% can be obtained Its structural characterization results are consistent with those reported in the literature Conclusion: salimabromide (1), a natural product, was synthesized in 17 steps There are two bright spots in the whole synthesis process, one is the acid catalyzed Wagner meerwein rearrangement / Friedel crafts cyclization to construct two adjacent quaternary carbon centers, the other is the [2 + 2] cycloaddition of the intermediate of ketene imine ions and the subsequent Baeyer Villiger oxidation to construct cyclopentalactone containing three stereocenters This study is of great significance for the subsequent synthesis of these compounds.