Synthesis of Mukonine and Seven Further 1-Oxygenated Carbazole Alkaloids

Abstract

As an intermediate in the synthesis of seven further 1-oxygenated 3-C 1 -substituted carbazole alkaloids, mukonine (1) was synthesized in 46% overall yield, starting from indole-3-carbaldehyde (12) with a Horner-Emmons reaction as the crucial step. From 1 , the other desired alkaloids were obtained in high yields. Among them, clausine E (6) and O -demethylmurrayanine (7) were synthesized for the first time.

Synthesis of Methylene‐Bridged Biscarbazole Alkaloids by using an Ullmann‐type Coupling: First Total Synthesis of Murrastifoline‐C and Murrafoline‐E

“…Based on that observation, we decided to synthesise bismurrayafoline-A (1)b ya pplying ad irect coupling of murrayafoline-A( 8a)a nd the para-nitrobenzoate 14 a.T hus, the ester group of 8e was first reduced with lithium aluminium hydride to provide 8a in high yield (Scheme 5). [9,24] Notably,t his approach led to the naturalp roduct 8a in three steps and 79 %o verall yield, which is the highest yield reported for the synthesis of murrayafoline-A (8a)s of ar.T he reactiono f8a and 14 a in the presence of copper(I) bromide, pyrrole-2-carboxylic acid, and potassium phosphate as base, which are the Ullmann conditions that were most successful for the coupling of 8e and 14 a,f inally provided 1 in 46 %y ield (Scheme 6). As observed before,t he Boc group of 14 a was cleaved under the reaction conditions.…”

“…Based on that observation, we decided to synthesise bismurrayafoline‐A ( 1 ) by applying a direct coupling of murrayafoline‐A ( 8 a ) and the para ‐nitrobenzoate 14 a . Thus, the ester group of 8 e was first reduced with lithium aluminium hydride to provide 8 a in high yield (Scheme ) . Notably, this approach led to the natural product 8 a in three steps and 79 % overall yield, which is the highest yield reported for the synthesis of murrayafoline‐A ( 8 a ) so far.…”

“…This second approachs tarted with the oxidation of 9a by using DDQ to obtain the corresponding aldehyde murrayacine (24) [29] in 96 %yield (Scheme 9). [6c, l] Boc-Protection of the carbazole nitrogen atom of 24 followed by reduction of the carbaldehydet oahydroxymethyl group and activation of the latter as para-nitrobenzoate provided 25 in 87 %y ield over three steps.C oupling of para-nitrobenzoate 25 and 8a by application of the conditions described above directly provided 6; thus, biscarbazole 6 was obtained in nine steps and 15 %o verall yield based on commercially available compounds.…”

Biarylic Biscarbazole Alkaloids: Occurrence, Stereochemistry, Synthesis, and Bioactivity

“…Due to the endocyclic nitrogen, carbazoles have a high electron density throughout the whole aromatic framework, so that direct electrophilic halogenations were not expected to proceed with high regioselectivity, particularly not for the desired—but sterically hindered—position 2. Therefore, a directed ortho ‐metalation (DoM)40 strategy was chosen for this purpose, giving best results with a combination of two directing groups, 3‐hydroxymethyl and 1‐methoxymethoxy, as present in carbazole 42 , which was prepared from indole‐3‐carbaldehyde ( 36 ) 2,37,41. After lithiation with n BuLi, the resulting intermediate was quenched with (CBrCl 2 ) 2 as the electrophilic bromine source 41.…”

“…10). 2,37,41,45 Prefixation of these two compounds by esterification was achieved in 86% yield using dicyclohexylcarbodiimide (DCC) and 4‐(dimethylamine) pyridine (DMAP) 45. The Pd‐mediated, “redox‐neutral” intramolecular coupling of ester 56 was hampered by the electron‐rich nature of the carbazole nuclei, making stoicheometric quantities of Pd(OAc) 2 necessary to achieve a still moderate coupling yield of 35%.…”