Domino Reaction for the Synthesis of Polysubstituted Pyrroles and Lamellarin R

Abstract

A three-component annulation reaction was developed for the synthesis of pyrroles, a class of compounds with various properties valuable to biomedical and polymer industries. Treatment of α-silylaryl triflates, Schiff bases, and alkynes generated polysubstituted pyrroles in good yields (61–86%) with regioselectivity. This domino reaction involved completion of five sequential steps in a single flask, which comprised aryne formation through 1,2-elimination, their alkylation by Schiff bases through 1,2-addition, 1,4-intramolecular proton transfer, Hüisgen 1,3-dipolar cycloaddition, and dehydrogenative aromatization. It was then successfully applied as the key step in the synthesis of the natural product lamellarin R. This new reaction represents an efficient, sustainable process for the production of chemical materials.

Synthesis of lamellarin R, lukianol A, lamellarin O and their analogues

“…A key feature in the synthesis of lamellarin alkaloids type III is the construction of the aryl-substituted pyrrole ring, which can be categorized into two different synthetic approaches, that is, functionalization of a simple pyrrole core and synthesis of the functionalized pyrrole moiety from the appropriate precursors. The former is represented by the works of Banwell, 6 Iwao, 7 Wong 8 and Okano's groups, 9 whereas the latter is exemplied by Boger,10 Vazquez, 11 F} urstner, 12 Jia, 13 Hwu, 14 Iwao, 15 and Yang's groups. 16 While the total synthesis of lamellarin alkaloids type III has been documented by the aforementioned researchers, the development of more efficient and greener synthesis of these natural products along with their analogues leaves more room for improvement.…”

“…Thus, the protection of the two hydroxyl groups on the pyrrole ring with a functional group other than OMe seems inevitable for the preparation of lamellarin O. Scheme 4 shows the synthesis of lamellarin O (13) from the OBn protected (E)-1-(benzyloxy)-4-(2-nitrovinyl)benzene (14). Similar to that of lamellarin R, the synthesis started with bromination of 14 with Br 2 to give the brominated 15.…”

Asymmetric Synthesis of 3‐Pyrrolines through an Aryne‐Induced Domino Process

“…These results indicate that the [1,4]-sigmatropic proton shift overwhelmed the [1,5]-proton shift (11 a @ 11 b); a few examples of this occurrence exist in the literature. [39,[53][54][55] This phenomenon may be associated with the phenyl carbanionic center with an sp 2 character. The phenyl ring and the iminium N + =C double bond in 11 a are conjugated, leading to coplanarity of the C1À N + À C3À C4 four atoms and the p orbital of the electron pair that is attached to the phenyl ring.…”

“…This reaction, however, did not proceed at all in acetonitrile, which we used successfully in earlier syntheses of imidazolidines, [39a] pyrrolidines, [39a] and pyrroles. [55] Under aerobic conditions, pyrroles are generated as the exclusive products. [55] The Hüisgen 1,3-dipolar cycloaddition was the key step for the generation of the two stereogenic centers in the nucleus of 3-pyrrolines.…”

Mild and Efficient Copper-Catalyzed Synthesis of Trisubstituted Pyrroles

“…Recently, the Hwu group demonstrated the state-of-art technique for the synthesis of substituted pyrroles using benzyne chemistry. 41 In the presence of Schiff base, alkyne, and silylaryl triflates, poly functionalized pyrroles can be achieved at room temperature with good to high yields. Even though many synthetic methods exist for the synthesis of pyrroles; mild, efficient, and economic methods are always in need and should be compatible with a vast library of substrates and functional groups.…”