Enantioselective Synthesis of (S)-(+)-Pantolactone

Abstract

[reaction: see text] The Prins reaction of a chiral alkylidene morpholinone derived from (1R,2S)-ephedrine and 3-methyl-2-oxobutanoic acid proceeds with good diastereoselectivity to generate a spiro bis-acetal. Lewis acid mediated diastereoselective reductive cleavage of the spiro acetal and subsequent removal of the ephedrine portion generates a alpha-hydroxy-gamma-methoxy carboxamide which is readily converted to (S)-(+)-pantolactone with high enantiomeric excess.

Dimethyl [(2R,3R,5S)‐5‐phenylmorpholine‐2,3‐diyl]diacetate as a Designer Substrate in the Syntheses of Important Heterocyclic Scaffolds

“…[8] Enthused by the successful synthesis of 1, we set out to explore its transformation to various heterocyclic scaffolds (2)(3)(4)(5). (2) is extensively utilized for synthesizing the Geissman-Waiss lactone; [9] as well as a precursor in the syntheses of various pyrrolizidine alkaloids, [10] and a key intermediate for synthesizing pyrrolidine trans-lactones.…”

“…Towards this endeavour, we designed dimethyl [(2R,3R,5S)-5-phenylmorpholine-2,3-diyl]diacetate (1) for constructing a variety of heterocyclic scaffolds, such as methyl [(2R,3S)-3-hydroxy-5-oxopyrrolidin-2-yl]acetate (2), methyl [(2R,3S)-3-amino-5-oxotetrahydrofuran-2-yl]acetate (3), (3R,4S)-4-aminohexane-1,3,6-triol (4), and 2-[(2R,3S)-3-aminotetrahydrofuran-2-yl]ethanol (5), as shown in Scheme 1. Morpholine or 1,4-oxazine structural motifs, apart from being a part of various molecules that possess biological and pharmaceutical activities, [2] are also finding applications as organocatalysts, [3] chiral auxiliaries, [4] chiral templates [5] and synthetic precursors. [6] The synthetic intermediates and precursors that are made from 1 are either used in the synthesis of biologically active natural products and pharmaceuticals or are substructures of natural products.…”

Asymmetric Synthesis of Pantolactone: Recent Advances

“…For example, in 2000, Pansare et al used chiral (1R,2S)-ephedrine as a chiral source for the synthesis of D-PL (Scheme 22). [74] Following the acylation of (1R,2S)-ephedrine hydrochloride 63 with 3-methyl-2-oxobutanoyl chloride 64, hemiacetal 65 was generated, which was subsequently dehydrated to the chiral acrylamide 66. The Prins reaction of 66 with paraformaldehyde in acetic acid at 75-80 °C in the presence of a catalytic amount of concentrated sulfuric acid produced spiroacetal 67 in a 70-72 % yield.…”

The Prins Reaction: Advances and Applications

“…pound 147 as the major diastereomer (up to 54% ee) (Scheme 31) [12]. Changing the solvent to acetic acid was beneficial for the reaction, and so compound 152 reacted with paraformaldehyde in the presence of a catalytic amount of sulfuric acid to provide compound 153 in 72% yield (Scheme 32) [50]. Aqueous formaldehyde reacted with compound 152 in dioxane at 80 ºC, under sulfuric acid catalysis, giving the corresponding 1,3-dioxane derivative 153 in 41% yield, as a single diastereomer.…”