Rational Approach to Selective and Direct 2-O-Alkylation of 5,6-O-Isopropylidine-l-ascorbic Acid

Abstract

l-Ascorbic acid is a versatile radical scavenger widely distributed in aerobic organisms that plays a central role in the protection of cellular components against oxidative damage by free radicals and oxidants. It also functions as a physiological reductant for key enzymatic transformations in catecholamine neurotransmitters, amidated peptide hormones, and collagen biosynthetic pathways. Simple derivatives of l-ascorbic acid have been shown to possess antioxidant, antitumor, and immunostimulant activities. The antioxidant and redox properties of l-ascorbic acid are closely associated with the electron-rich 2,3-enediol moiety of the molecule, and therefore, selective functionalization of the 2- and 3-OH groups is essential for the detailed structure-activity studies. Reactions of 5- and 6-OH-protected ascorbic acid with electrophilic reagents exclusively produce the corresponding 3-O-alkylated products under mild basic conditions due to the high nucleophilicity of the C-3-OH. Based on the density functional theory (B3LYP) electron density calculations, we have devised a novel and general method for the direct alkylation of the 2-OH group of ascorbic acid with complete regio- and chemoselectivity. We have also carried out a complete spectroscopic analysis of two complementary series of 2-O-acetyl-3-O-alkyl- and 2-O-alkyl-3-O-acetylascorbic acid derivatives to define their spectroscopic characteristics and to resolve common inconsistencies in the literature.

Synthesis of Poly(vitamin C) through ADMET

“…Therefore, it has always been complicated to make selective chemical reactions based on the hydroxyl groups. Fortunately, with the development of novel alkylation and acylation methods, it is no more problematic to make selective modification through the hydroxyl groups. Given the literature method, we first protected C5 and C6 hydroxyl groups of l ‐ascorbic acid in order to yield 2 .…”

“…Moreover, ascorbic acid is widely employed in the food industry as an additive to extend shelf life of food products and beverages . Thanks to the well‐established synthetic methods, the synthesis of several compounds of biological importance through l ‐ascorbic acid has been achieved over the last two decades . The popularity of l ‐ascorbic acid, on the other hand, has accelerated since 2002 after the development of copper‐catalyzed azide–alkyne cycloaddition (CuAAC) reaction, also well‐known by its popular name, “click chemistry.” The sodium salt form of l ‐ascorbic acid, sodium ascorbate, has been proven to be the most suitable reducing agent to produce in situ Cu(I), one of the crucial reagents for CuAAC reaction from Cu(II) source, especially in aqueous medium …”

Ascorbate Analogs for Use in Medical Imaging: Synthesis and Radical Scavenging Activity of 5-O-(4'-Iodobenzyl)-L-ascorbic Acid

“…[15][16][17] We envisioned that derivatization of the C 5 -oxygen of AsA could be accessed by suitable manipulation of the protection and deprotection processes of the fourhydroxyl functional groups of AsA. However, a general problem of protected AsA derivatives is that a secondary proton at C 4 , adjacent to the enediol framework, is often susceptible to abstraction by a base, followed by an E2 elimination process leading to unsaturated 4,5-didehydro compounds.…”

Formation of L‐Threonic Acid from L‐Ascorbic Acid Oxidative Ring Opening and its Coordination to PtII: X‐ray Crystal Structures of [Pt(threonato‐O,O′)(PPh3)2] and [Pt(oxalato)(PPh3)2]

“…In order to prepare a L ‐ascorbic acid derivative bearing the 2‐OH hydroxy group as the only available oxygen donor, we attempted to obtain the 3‐ O ‐methylated form of 5,6‐ O ‐isopropylidene L ‐ascorbic acid through a modified version of the route reported by Wimalasena, which provided for the use of MeI in basic dmso 4. In order to avoid the use of toxic high‐boiling dmso, we tried to replace it with methanol.…”