Regioselective Ring Opening of Malic Acid Anhydrides by Carbon Nucleophiles. Application in the Synthesis of Chiral Tetronic Acids

Abstract

S-Malic acid is an important chiral building block which has found wide application in the enantioselective synthesis of chiral compounds. 1 Manipulation of this polyfunctional synthon requires the selective protection of the different functionalities and the distinction of the two carboxyl groups present. The O-protected hydroxysuccinic anhydrides (I) derived from malic acid offer a unique way to achieve both these tasks. These anhydrides react regioselectively at the C-2 site with oxygen and nitrogen nucleophiles providing malic acid monoesters 2 and monoamides, 3 respectively. However, no report has appeared concerning similar behavior toward carbon nucleophiles.

Metal-Catalyzed and Metal-Mediated Approaches to the Synthesis and Functionalization of Tetramic Acids

“…An interesting feature of this study is the incorporation of 3-alkyl and 3-aryl substituents using LDA at −78 • C, without racemization. A similar starting material, O-protected hydroxyl succinic anhydride (malic acid anhydride), has been used from the same group [89] for the synthesis of chiral tetronic acids. In the second, 2-methyl-4-benzylidene-5(4H)-oxazolone 24 was found to serve successfully as both a protected and an activated α-amino acid.…”

Tetramic and Tetronic Acids as Scaffolds in Bioinorganic and Bioorganic Chemistry

“…Several methodologies include Dieckmann cyclization [ 23 ], cycloaddition [ 24 ], oxidation [ 25 ], Wittig-Claisen [ 26 ], lactonization [ 27 ], and enzymatic reactions [ 28 ]. A few years ago, the synthesis of 3-acyl-5-methoxycarbonyl tetronic acids has been reported from our research group [ 29 ]. A new strategy for the synthesis of functionalized tetronic acids was developed by Schobert and coworkers [ 30 ], applying the “domino” process, which comprises of the reaction between the esters of α -hydroxy acids and the cumulated phosphorus ylide ketenylidenetriphenylphosphorane ( Scheme 4 ).…”

A novel synthetic approach to the thiotetronic ring system, the key intermediate for thiolactomycin analogues

“…In the course of our research programme on the use of enolic β-dicarbonyl compounds for the synthesis of tetronic 18,19 and tetramic acids [20][21][22] and 2-amino-3-substituted heterocyclic compounds, 23,24 we have developed a new synthetic sequence for the construction of functionalized thiotetronic acids. In this paper we present a new synthetic approach to thiotetronic acid analogues bearing various functional groups at the C-3 (COR, CO 2 R) and C-5 (alkyl) positions of the thiolactone ring.…”