Solvent Effect Observed in Nucleophilic Substitution of 4′-(Benzoyloxy)cordycepin with AlMe₃: Stereochemical Evidence for S_Ni Mechanism

Abstract

Nucleophilic substitution between the 4'-benzoyloxy derivative of cordycepin (3'-deoxyadenosine) and AlMe(3) proceeds mostly with retention of configuration at the 4'-position: the 4'-benzoyloxy substrate having the beta-d-configuration (8a) gave the 4'-methylated beta-d-nucleoside (9a) with a high diastereomeric excess, while the substrate 8b having the opposite 4'-configuration gave the corresponding alpha-l-isomer (9b) with a comparatively lower stereoselectivity. The S(N)i mechanism is proposed for this reaction (from 8 to 9). The polarity of the solvent has a significant influence on the stereoselectivity, especially for the formation of 9b.

A review of methods to synthesise 4′-substituted nucleosides

“…The authors ascribe this to an S N i (ion-pair) mechanism. 36 Higher selectivities were observed in the less polar solvent carbon tetrachloride than were observed when dichloromethane was used, supporting the ion-pair mechanism.…”

“…Ozonolysis was used to liberate the aldehyde required for lactonisation. Johnson and Kozak used the same synthon (36) to introduce a trifluoromethyl group to the 4′-position using Rupperts reagent and TBAF (compound 38). 21 This resulted in a 4 : 1 mixture of isomers in favour of the desired D-Ribo isomer.…”

Inverse Neighboring Group Participation: Explanation of an Unusual S→N Alkyl Migration of Isothiuronium Salts Containing a Lactone Group

“…It was proposed for intramolecular decomposition of alkyl chlorosulfites, for the reaction of cumylarenesulfonates and anilino thioethers with anilines and especially for some glycosyltranferase-catalyzed reactions . On the other hand, an S N 1 reaction proceeding through an intimate ion pair can also explain the retention of configuration . Moreover, most quantum chemical calculations give energy barriers of 170–200 kJ·mol –1 higher for front-side attack as compared to the classical back-side S N 2 reaction pathway although the difference steeply decreases for protonated alcohols and amines containing bulky alkyl group .…”

Phenylsulfanylation of 3′,4′-Unsaturated Adenosine Employing Thiophenol-N-Iodosuccinimide Leads to 4′-Phenylsulfanylcordycepin: Synthesis of 4′-Substituted Cordycepins on the Basis of Substitution of the Phenylsulfanyl Leaving Group

“…7 Radical-mediated deiodination of the resulting adduct 3 furnished 4′-benzoyloxycordycepin (4), which served as a useful precursor for the synthesis of the novel 4′-carbon-substituted analogues 5 by nucleophilic substitution of the benzoyloxy leaving group with organosilicon or organoaluminum reagents. 8 Phenylthioglycosides have been utilized as stable and useful glycosyl donors for the synthesis of O-glycoside, 9 glycosyl fluoride, 10 and C-glycoside 11 through activation of the phenylsulfanyl group under neutral conditions. We envisioned that the versatility of the phenylsulfanyl substituent as a leaving group would enable the synthesis of novel 4′-substituted derivatives of cordycepin by substitution reactions of the phenylsulfanyl group.…”

“…In the course of our ongoing research on the synthetic chemistry of unsaturated sugar nucleosides, we have recently reported the iodobenzoyloxylation of the 3′,4′-unsaturated adenosine derivative 2 utilizing N -iodosuccinimide (NIS) and benzoic acid (Scheme ) . Radical-mediated deiodination of the resulting adduct 3 furnished 4′-benzoyloxycordycepin ( 4 ), which served as a useful precursor for the synthesis of the novel 4′-carbon-substituted analogues 5 by nucleophilic substitution of the benzoyloxy leaving group with organosilicon or organoaluminum reagents …”