An Economical Route to Lamivudine Featuring a Novel Strategy for Stereospecific Assembly

Abstract

An economical synthesis of lamivudine was developed by employing a new method to establish the stereochemistry about the heterocyclic oxathiolane ring. Toward this end, an inexpensive and readily accessible lactic acid derivative served the dual purpose of activating the carbohydrate's anomeric center for N-glycosylation and transferring stereochemical information to the substrate simultaneously. Both enantiomers of the lactic acid derivative are available, and either β-enantiomer in this challenging class of 2′-deoxynucleoside active pharmaceutical ingredients can be formed.

Advances on Greener Asymmetric Synthesis of Antiviral Drugs via Organocatalysis

“…Pharmaceuticals 2021, 14, x FOR PEER REVIEW 4 of 18 Indinavir AIDS, HIV-1 protease inhibitor (a) (R)-glycidol as starting material [34] b) from indanone via enantioselective ester hydrolysis with Rhizopus oryzae [35] (c) (1S,2R)-cisaminoindanol as starting material [36] Lamivudine AIDS and HBV, reverse transcriptase inhibitor hydrolysis with Rhizopus oryzae [35] (c) (1S,2R)-cisaminoindanol as starting material [36] Lamivudine AIDS and HBV, reverse transcriptase inhibitor (a) enzymatic dynamic kinetic resolution [37] (b) (S)-lactic acid as starting material [38] (c) L-menthol as chiral auxiliary [39] 10 Maraviroc AIDS, antagonist of the CCR5 receptor (a) (S)-tertbutanesulfinamide as chiral auxiliary [40] hydrolysis with Rhizopus oryzae [35] (c) (1S,2R)-cisaminoindanol as starting material [36] Lamivudine AIDS and HBV, reverse transcriptase inhibitor (a) enzymatic dynamic kinetic resolution [37] (b) (S)-lactic acid as starting material [38] (c) L-menthol as chiral auxiliary [39] 10 Maraviroc AIDS, antagonist of the CCR5 receptor (a) (S)-tertbutanesulfinamide as chiral auxiliary [40]…”

Synthetic strategies toward 1,3-oxathiolane nucleoside analogues

“…Further, cyclocondensation of 47 with 2-mercaptoacetaldehyde diethyl acetal (3nb) in the presence of p-TSA in benzene solvent afforded 1,3oxathiolane intermediate (±)-2,2-bis(acetoxymethyl)-5-ethoxy-1,3-thioxalane (48). More recently, an approach developed by Snead et al [53] at the Medicines for All Institute used lactic acid derivatives to test the impact of a chiral auxiliary on N-glycosylation. Compound 50 was synthesized by ozonolysis of alkene 3rb, followed by reaction of aldehyde (generated in situ from alkene) with 1,4-dithiane-2,5-diol (3q).…”

“…Sulfenyl chloride chemistry was used to synthesize the oxathiolane precursor 56a from acyclic precursors. The method used chloroacetic acid (53), vinyl acetate, sodium thiosulfate, and water to construct the oxathiolane moiety. The use of sulfenyl chloride provided a new method to access such oxathiolanes (Scheme 16).…”

“…More recently, an approach developed by Snead et al [ 53 ] at the Medicines for All Institute used lactic acid derivatives to test the impact of a chiral auxiliary on N-glycosylation. Compound 50 was synthesized by ozonolysis of alkene 3rb , followed by reaction of aldehyde (generated in situ from alkene) with 1,4-dithiane-2,5-diol ( 3q ).…”

“…Snead and co-workers [ 53 ] recently developed a new approach for stereoselective nucleoside synthesis that enables a cost-effective approach to lamivudine ( 1 , Scheme 53 ). The synthesis of lamivudine ( 1 ) was established by employing a method that defines the stereochemistry at the oxathiolane moiety.…”