Model Construction for the A–B–C Ring System of Lysergic Acid via Vilsmeier–Haack‐Type Cyclization of 1H‐Indole‐4‐propanoic Acid Derivatives

Abstract

Vilsmeier -Haack-type cyclization of 1H-indole-4-propanoic acid derivatives was examined as model construction for the A -B -C ring system of lysergic acid (1). Smooth cyclization from the 4 position of 1H-indole to the 3 position was achieved by Vilsmeier -Haack reaction in the presence of K 2 CO 3 in MeCN, and the best substrate was found to be the N,N-dimethylcarboxamide 9 ( Table 1). The modified method can be successfully applied to an a-amino acid derivative protected with an N-acetyl function, i.e., to 27 (Table 2); however, loss of optical purity was observed in the cyclization when a chiral substrate (S)-27 was used (Scheme 5). On the other hand, the intramolecular Pummerer reaction of the corresponding sulfoxide 20 afforded an S-containing tricyclic system 22, which was formed by a cyclization to the 5 position (Scheme 3).1. Introduction. -Lysergic acid (1), a tetracyclic indole derivative with two stereogenic centers, is the core unit of ergot alkaloids showing wide spectra of biological activities [1] such as prolactin inhibition, anti-Parkinsonian effect, and depression of hypertension. The total synthesis of racemic 1 has been reported by nine research groups [2], and two groups have successfully achieved the asymmetric synthesis [3].Recently, we have explored a novel aziridination from guanidinium ylides and aromatic (or unsaturated) aldehydes, applicable to asymmetric synthesis [4], and designed the atom-economical synthesis of bioactive N-containing compounds using the formed aziridine as a key synthetic intermediate. Our retro-synthetic strategy of lysergic acid (1) is shown in Scheme 1, in which all the C-and the N-units of the aziridine 2, derived from guanidinium ylide 3 and 1H-indole-4-carboxaldehyde 4, are incorporated in the lysergic acid structure during the synthesis. One of the key reactions is the construction of ring C via cyclization from the 4 position of the 1H-indole skeleton 2 to its 3-position. Such cyclizations had already been examined by four groups [2i] [5], among which Nedelec and Raincy [5a] reported the application of the Vilsmeier -Haack reaction to 1H-indole-4-propanamide in their patent. Thus, we extensively examined the cyclization based on their methodology and, in this paper, describe experimental results obtained by using varieties of 1H-indole-4-propanoic acid derivatives.

Semisynthesis and Biological Activity of Stemofoline Alkaloids

“…The mesyl group could not be displaced by treatment with LiEt 3 BH but did react with sodium thiophenolate to give the corresponding thioether as a mixture of ( Z )- 13 and ( E )- 14 isomers (Scheme ). In an attempt to reduce the number of steps involved in this synthesis, the alcohol 12 was displaced directly by diphenyldisulfide and tributylphosphine rather than going through the mesylate (Scheme ) . It was observed that this reaction also resulted in isomerization of the C-11−C-12 double bond to form the separable Z - and E -isomers 13 and 14 , respectively.…”

“…In an attempt to reduce the number of steps involved in this synthesis, the alcohol 12 was displaced directly by diphenyldisulfide and tributylphosphine rather than going through the mesylate (Scheme 3). 26 It was observed that this reaction also resulted in isomerization of the C-11-C-12 double bond to form the separable Z-and E-isomers 13 and 14, respectively. This isomerization was thought to have occurred by attack of the thiophenolate ion at C-11 of 13, followed by bond rotation around the C-11-C-12 bond and then elimination of the thiophenolate ion, as illustrated by the mechanism in Scheme 4.…”

Discovery of a Phenylamine-Incorporated Angucyclinone from Marine Streptomyces sp. PKU-MA00218 and Generation of Derivatives with Phenylamine Analogues

“…Thus, compound 1 was identified as an unusual phenylamine-incorporated angucyclinone (2-(2-(hydroxymethyl)-3-methoxyphenyl)-7-methyl-1-phenylbenzo­[ cd ]­indol-3­(1 H )-one) (Figure ). Until now, only a few compounds containing a benzo­[ cd ]­indol-3­(1 H )-one moiety have been reported, with 0231A and 0231B as the only two natural products, and all others as intermediates in the total synthesis of 0231B or ergot alkaloids . Therefore, compound 1 represents a new member of angucyclinones featuring a unique 1-phenylbenzo­[ cd ]­indol-3­(1 H )-one moiety.…”

“…The benzo­[ cd ]­indol-3­(1 H )-one ring system has been synthesized in the total synthesis of 0231B and ergot alkaloids. There are four methods reported to construct this ring system, with all of them needing catalysts and some needing very low (−78 °C) or high (80 °C) temperatures (Figure S7). The discovery of nonenzymatic conversion from 2 to 1 in this work provides a more mild and efficient method to construct the benzo­[ cd ]­indol-3­(1 H )-one ring system (Figure C).…”

Rh-Catalyzed Asymmetric Hydrogenation of Cyclic α-Dehydroamino Ketones

“…However, the hydrogenation of cyclic α-acyl enamides, especially those bearing an endocyclic α-acyl group, remains uncommon (Figure , red-colored structures, X = C, N, O, S). , On the other hand, compared to the extensive research carried out with α-dehydroamino acids, esters, and amides, only one report has been published concerning the asymmetric hydrogenation of α-dehydroamino ketones and none for cyclic substrates, though chiral cyclic α-amino ketones are very useful structural motifs found in a range of bioactive molecules and can be easily derivatized to give versatile chiral cyclic β-amino alcohols and amines . Previously, chiral cyclic α-amino ketones were typically synthesized via intramolecular Friedel–Crafts reactions of chiral α-amino acids and via α-aminations of cyclic ketones or their equivalents. − In addition to these procedures being inefficient, these methodologies also suffer from problems of partial racemization of the chiral α-amino ketones because of their facile enolization under acidic and alkaline conditions. Therefore, from both theoretical and practical perspectives, synthesis of chiral cyclic α-amino ketones via the asymmetric hydrogenation of cyclic α-dehydroamino ketones with high chemoselectivity (distinguish the reductive CC and CO bonds) and enantioselectivity is greatly desired.…”