Methionine and Buthionine Sulfoximines: Syntheses under Mild and Safe Imidation/Oxidation Conditions

Abstract

Methionine and buthionine sulfoximines (MSO and BSO) are non-natural amino acids known to inhibit the biosynthesis of glutathione (GSH). The current syntheses of these biologically active molecules involve harsh reaction conditions and the use of hazardous reagents for the sulfur imidation. Here, improved syntheses of MSO and BSO are presented including safe and mild one-pot imidation/oxidation sequences and single-step deprotections of three different functionalities.Methionine sulfoximine (MSO, 1), the first example of a sulfoximine ever described, was isolated from freshly milled wheat that had been treated with nitrogen trichloride. [1] The interesting biological profile of MSO ( Figure 1) attracted immediate attention, [2] and has provided a useful starting point for future/further investigations into the application of sulfoximine derivatives in a medicinal chemistry setting. [3] MSO interacts with g-glutamylcysteine synthetase, which is an essential enzyme in the glutathione (GSH, 3) synthesis, and irreversibly inhibits glutamine synthetase. [4] A Scheme 3. Synthesis of MSO via an N-nosyl sulfoximine.Scheme 4. Synthesis of MSO and BSO via N-acyl sulfoximines.

Sulfur Imidations by Light‐Induced Ruthenium‐Catalyzed Nitrene Transfer Reactions

“…Accordingly, N ‐acyl sulfoximines 5 could be rapidly accessed in yields of up to 99 % under mild reaction conditions starting from the corresponding sulfides 2 (Scheme , top). This protocol was subsequently applied to the synthesis of methionine sulfoximine (MSO, 6a ) and buthionine sulfoximine (BSO, 6b ),10 which are two well‐established chemotherapeutic agents that are known to reduce the level of glutathione in cells (Scheme , bottom). A comparison of the “one‐pot” imidation/oxidation procedure with alternative approaches towards MSO/BSO revealed the superiority of the former method.…”

Synthesis of Methionine‐Derived Endocyclic Sulfilimines and Sulfoximines

“…They have found many applications as chiral auxiliaries, as ligands in asymmetric catalysis, as activating groups in C–H activation or ortho ‐lithiation, as precursors of heterocycles, and in the preparation of other sulfurated functions . Surprisingly, sulfoximines have long been neglected in medicinal chemistry despite the early discovery of biological activities of methionine sulfoximine ( 3 , MSO) and buthionine sulfoximine ( 4 , BSO), as a glutamine synthetase inhibitor and a specific and competitive inhibitor of γ‐glutamylcysteine synthetase, respectively (Scheme ). Thus, only few compounds containing the sulfoximine moiety have emerged, such as potent kinase inhibitors (BAY‐1143572,[10a] BAY‐1000394,[10b] and AZD‐6738) and insecticides (Sulfoxaflor).…”

Greener Preparation of 5‐Ethyl‐4a‐hydroxyisoalloxazine and Its Use for Catalytic Aerobic Oxygenations

“…In addition to 5a , 4‐methylthioanisole ( 5b ), 4‐methoxythioanisole ( 5c ), and dioctyl sulfide ( 5d ) were tolerated and all the corresponding sulfoxides ( 6a – 6d ) were isolated through a chromatographic purification in high yields (Table , entries 1–4). l ‐Methionine ( 5e ) could also be oxidized into biologically and synthetically important l ‐methionine sulfoxide ( 6e ), which was readily isolated in 95 % yield only by filtration and washing with general solvents (entry 5).…”