Synthesis of Oxacycles Employing the Oxa‐Pictet–Spengler Reaction: Recent Developments and New Prospects

Abstract

The oxa‐Pictet–Spengler cyclization is the oxygen variation of the Pictet–Spengler reaction, in which an aromatic alcohol component (generally a β‐arylethyl alcohol) reacts with acarbonyl component (aldehyde, ketone or their masked derivatives), to yield a 1‐substituted (or 1,1′‐disubstituted)pyran fused to the aromatic ring system found in the starting alcohol. The transformation is usually promoted by Brønsted and Lewis acids. Intramolecular versions of the reaction are also known, where both components are mutually masked as an acetal. Discussed here are aspects concerning the most recent developments and new applications of this useful reaction, including the scope and limitations of new promoters, and new mechanistic pictures of this transformation. The use of novel stereochemical control strategies and the application of the reaction to the synthesis of natural products and their analogs, as well as to accessing fully synthetic bioactive compounds and new ring systems are presented, and chiral versions of the oxa‐Pictet–Spengler are also analyzed.

Synthesis and Biological Evaluation of 7‐Deoxy Analogues of the Human Rhinovirus 3C Protease Inhibitor Thysanone

“…We planned to synthesize 2 by using a key oxa-PictetSpengler reaction [10] of naphthalene 3 with dimethoxymethane (4) to provide the complete carbon framework of the target compound 2 (Scheme 1). This approach compleScheme 1.…”

HPLC Monitoring of Acid Catalyzed Conversion of 7-Ethyltryptophol to Methyl Ester of Etodolac

“…The structure of etodolac methyl ester (Scheme 1) was confirmed by 1 H, 13 C and 1 H-13 C HMBC NMR spectroscopy using Bruker Avance III HD 400 MHz spectrometer, CDCl3 as solvent and tetramethylsilane (TMS) as internal standard. NMR data for isolated etodolac methyl esters were all analogous and were as follows: 1 …”

“…The synthetic procedures for the preparation of etodolac and its precursors were presented in the past by several authors [9][10][11][12][13][14] . The key intermediate in the etodolac synthesis is its alkyl ester which is obtained by the oxa-Pictet-Spengler reaction (Scheme 1) promoted by different Brönsted and Lewis acids.…”

“…The key intermediate in the etodolac synthesis is its alkyl ester which is obtained by the oxa-Pictet-Spengler reaction (Scheme 1) promoted by different Brönsted and Lewis acids. [13] Since Lewis acids are often expensive and difficult to manage in productions on a larger scale, inorganic mineral acids (HCl, HBr, H2SO4, H3PO4) are preferred. [12] For example, in the report by Vigano and Colombo [12] the reaction of 7-ethyltryptophol with methyl 3-oxopentanoate, conducted in an apolar solvent (toluene), the amount of HCl or H2SO4 added was in a molar ratio from 0.5 to 5 with respect to 7-ethyltryptophol.…”

“…The preparation of etodolac methyl ester by oxa-Pictet-Spengler reaction starting from 7-ethyltryptophol with purity ranging from 79 to 95 % is reported in several patents. [13,14] Therefore, we have developed the HPLC method to monitor the oxa-Pictet-Spengler conversion of 7-ethyltryptophol to etodolac methyl ester over time. Based on the obtained kinetic profiles the optimal reaction conditions and parameters for the synthesis of etodolac methyl ester were selected.…”