Traceless Solid-Phase Synthesis of Ketones via Acid-Labile Enol Ethers: Application in the Synthesis of Natural Products and Derivatives

Abstract

In solid-phase organic synthesis, Wang resin is traditionally used for the immobilization of acids, alcohols, phenols, and amines. We report the use of Wang resin for the traceless synthesis of ketones via acid-labile enol ethers. We demonstrate the practicality of this synthetic strategy on the solid-phase synthesis of pyrrolidine-2,4-diones, which represent the core structure of several natural products, including tetramic acid. Base-triggered condensation of pyrrolidine-2,4-diones yielded 4-hydroxy-1,1′,2′,5-tetrahydro-2H,5′H-[3,3′-bipyrrole]-2,5′-diones.

Greening Solid-Phase Organic Synthesis: Environmentally Conscious Synthesis of Pharmaceutically Relevant Privileged Structures 5,6-Dihydropyridin-2(1H)-ones and Quinolin-2(1H)-ones

“…Traditional protocols were modified according to previously published procedures. ,, Protocols for the green approach follows.…”

“…On the basis of our previously published SPOS with intramolecular Wittig olefination as a key step leading to five-membered rings of tetramic acid derivatives (Scheme ), − we extend this solid-phase protocol to six-membered alicyclic and fused rings ( 14 – 16 , Figure ). Instead of α-amino acids, we utilized β-amino acids, such as β-alanine and substituted anthranilic acids.…”

Traceless Solid-Phase Organic Synthesis

“…Recently, the synthesis of acid-labile Wang resin-bound enol ethers via an intramolecular Wittig olefination of carboxylate esters and subsequent acid-mediated traceless release of ketones was reported. 378 The synthesis started with the acylation of Wang resin 2 with N-Fmoc-N-alkylated amino acids, and the Fmoc protecting group was removed (resin 1400, route A, Scheme 251). Alternatively, the hydroxyl group of the Wang resin was esterified with Fmoc-amino acid, and upon cleavage of the Fmoc group (resin 1401, route B), the primary amine was activated by 4-NsCl, and resulting sulfonamide 1402 was subjected to Mitsunobu alkylation with different alcohols.…”

Modern Strategies for Heterocycle Synthesis

“…More specifically, new intramolecular and intermolecular C-C and/or C-O bond-forming processes, with transition-metal catalysis or metal-free are summarized.In this Special Issue, Liu, Zhao and co-authors [6] report the first example of the generation of an indole/thiophene/pyrrole/pyridine/naphthalene/benzene-fused N-heterocycle library through an AuPPh 3 Cl/AgSbF 6 -catalyzed cascade reaction between amine nucleophiles and alkynoic acids in water. Low catalyst loading, good to excellent yields, high efficiency in bond formation (three new bonds together with two rings), excellent selectivity, great tolerance of functional groups, and extraordinarily broad substrate scope are features of this green cascade process.The advantages of solid-phase synthesis in time-efficient and traceless preparation of ketones via acid-labile enol ethers are described in the article by Krchňák and co-authors [7]. The practicality of this synthetic strategy on the solid-phase construction of pyrrolidine-2,4-diones, which represent the core structure of several natural products, including tetramic acid, is also demonstrated.…”

“…The advantages of solid-phase synthesis in time-efficient and traceless preparation of ketones via acid-labile enol ethers are described in the article by Krchňák and co-authors [7]. The practicality of this synthetic strategy on the solid-phase construction of pyrrolidine-2,4-diones, which represent the core structure of several natural products, including tetramic acid, is also demonstrated.…”