In situ complexation directs the stereochemistry of N-glycosylation in the synthesis of thialanyl and dioxolanyl nucleoside analogs

Enzymatic Kinetic Resolution of 1,3‐Dioxolan‐4‐one and 1,3‐Oxathiolan‐5‐one Derivatives: Synthesis of the Key Intermediate in the Industrial Synthesis of the Nucleoside Reverse Transcriptase Inhibitor AMDOXOVIR

“…After filtration the residue was purified by distillation to give the pure compound as a colorless liquid; yield: 37.6 g (0.18 mol, 63%); bp 52 ± 55 8C/0. Typical Procedure for the Preparation of (R)-(þ)-Isobutyric Acid 4-Oxo- [1,3]dioxolan-2-ylmethyl Ester (2) All enzymatic resolutions were performed according to this method.…”

“…For example, 2-(hydroxymethyl)-1,3-dioxolan-4-one (Scheme 1: X ¼ O, R ¼ H, TBDPS) is a key intermediate in the synthesis of Dioxolane-T, [1,2] whereas 2-(hydroxymethyl)-1,3-oxathiolan-5-ones (Scheme 1: X ¼ S, R¼ alkyl, silyl, acyl) can be used as building blocks for the preparation of the oxathiolanyl-nucleoside Coviracil ¾ . [2 ± 4] Due to its chemical nature this structure is not prone to resolution by crystallization of diastereomeric salts.…”

Lamivudine, an important drug in aids treatment

“…However, a precomplexation in situ between a proper Lewis acid and a ring heteroatom is capable of blocking the α-face, selecting the silylated base's attack to the β-face. This study also suggests the possibility of an intermediate, formed by the attack of one of the metal ligands (in this specific case, chloride) to the anomeric carbon, C-1, that also contributes to the stereocontrol of these kind of reactions (pathway B, Scheme 3) (17).…”

Synthesis of enantiomerically pure d-FDOC, an anti-HIV agent

“…11,12 Thus, when racemic acetate 1 was allowed to react with silylated 5-fluorocytosine, 2, in the presence of the oxaphilic Lewis acid, TiCl 3 (OiPr), under Vorbrü ggen conditions, 13 we observed b:a selectivity of >20:1, albeit only in moderate yield. More recently, we have found that the efficiency of this coupling reaction could be markedly improved (68% yield, b:a selectivity of >20:1) by using 2 equiv TiCl 3 (OiPr).…”

“…In retrospect, this result is consistent with the complexation hypothesis described above. 7,11,17 Indeed, Lewis acid complexation, while ensuring the good selectivity, simultaneously renders the C-O bond labile, resulting in the racemization of the chiral lactol acetate prior to glycosylation. In an effort to substantiate our complexation hypothesis, we employed a less oxaphilic Lewis acid catalyst in the glycosylation reaction.…”