Chemoselective and Enantioselective Oxidation of Indoles Employing Aspartyl Peptide Catalysts

Abstract

Catalytic enantioselective indole oxidation is a process of particular relevance to the chemistry of complex alkaloids, as it has been implicated in their biosynthesis. In the context of synthetic methodology, catalytic enantioselective indole oxidation allows a rapid and biomimetic entry into several classes of alkaloid natural products. Despite this potentially high utility in the total synthesis, reports of catalytic enantioselective indole oxidation remain sparse. Here we report a highly chemoselective catalytic system for the indole oxidation that delivers 3-hydroxy-indolenines with good chemical yields and moderate to high levels of enantio- and diastereoselectivity (up to 95:5 er and up to 92:8 dr. These results represent, to our knowledge, the most selective values yet reported in the literature for catalytic asymmetric indole oxidation). Furthermore, the utility of enantioenriched hydroxy-indolenines in stereospecific rearrangements is demonstrated.

Electrophilic carbonyl activation: competing condensative cyclizations of tryptamine derivatives

“…As a continuation of our prior studies on the oxidation, rearrangement 9,12 and cyclization 13 of 2-aryltryptamines, we were intrigued by the possibility of accessing potentially three unique modes of cyclization of 2-heteroaryltryptamine substrates in the presence of activated carbonyl electrophiles (Scheme 1). In our first attempt at evaluating the planned cyclization chemistry, we targeted 4-bromo-5,7-dimethoxyindole 14 and the tryptamine boronic ester 18 as the two coupling partners in the C–C bond-forming cross-coupling reaction (Scheme 3–4).…”

“…In our first attempt at evaluating the planned cyclization chemistry, we targeted 4-bromo-5,7-dimethoxyindole 14 and the tryptamine boronic ester 18 as the two coupling partners in the C–C bond-forming cross-coupling reaction (Scheme 3–4). Boronic ester 18 is easily accessed from tryptamine, 9a,12,15 and the indolyl coupling partner can be prepared from the known compound 12 (Scheme 3). 16 While methyl ester hydrolysis followed by decarboxylation 17 gave substrate 14 for exploratory studies, 18 the same synthetic sequence failed to provide 17 , which contained a masked phenol for carbocation trapping under C3-cyclization conditions (pathway A, Scheme 1), owing to the sensitivity of silyl ether 15 19 to basic hydrolysis conditions.…”

“…The cross-coupling reaction between indole bromide 17 and tryptamine boronic ester 18 12,15 gave heterodimer 19 in 78% yield (Scheme 4). Bisindole 19 was then converted to the cyclization precursor by first unmasking the primary amine via hydrazinolysis to provide amine 20 .…”

“…10 These studies have focused on the oxidation and cyclization of a variety of tryptamine substrates that occur primarily at the C2 and C3 positions. The combination of our prior strategies for rapid synthesis of 2-(2'-indolyl)-tryptamines, 9 2-(7'-indolyl)-tryptamines, 12 and our interest in spirocyclization of tryptamines 13 provided a unique opportunity to examine the competing cyclization manifolds available to 2-(4'-indolyl)-tryptamine such as 5 (Scheme 1). Herein we present our studies on the cyclization reactions of bisindoles and detail our results in securing a challenging spirocyclization using a carbamoyl chloride substrate.…”

An Overview of the Different Types of Catalysts in Organic Synthesis

“…A utilização de derivados peptídicos como organocatalisadores na reação de oxidação quimiosseletiva e enantiosseletiva de indóis foi descrita por Miller e colaboradores. 125 Essa é ferramenta de extrema relevância, uma vez que possibilita a construção de alcaloides estruturalmente complexos.…”