Investigation of Diastereoselective Acyclic α-Alkoxydithioacetal Substitutions Involving Thiacarbenium Intermediates

Abstract

Reported herein is an experimental and theoretical study that elucidates why silylated nucleobase additions to acyclic α-alkoxythiacarbenium intermediates proceed with high 1,2-syn stereocontrol (anti-Felkin-Anh), which is opposite to what would be expected with corresponding activated aldehydes. The acyclic thioaminals formed undergo intramolecular cyclizations to provide nucleoside analogues with anticancer and antiviral properties. The factors influencing the selectivity of the substitution reaction have been examined thoroughly. Halothioether species initially form, ionize in the presence (low dielectric media) or absence (higher dielectric media) of the nucleophile, and react through SN2-like transition structures (TS A and D), where the α-alkoxy group is gauche to the thioether moiety. An important, and perhaps counterintuitive, observation in this work was that calculations done in the gas phase or low dielectric media (toluene) are essential to locate the product- and rate-determining transition structures (C-N bond formation) that allow the most reasonable prediction of selectivity and isotope effects for more polar solvents (THF, MeCN). The ΔΔG(⧧) (G(TSA-TSD)) obtained in silico are consistent with the preferential formation of 1,2-syn product and with the trends of stereocontrol displayed by 2,3-anti and 2,3-syn α,β-bis-alkoxydithioacetals.

Diastereoselective Synthesis of C2′-Fluorinated Nucleoside Analogues Using an Acyclic Approach

“…The Gibbs free energy difference between these TS corresponds to 1.4 kcal/mol in THF at 0 °C and thus an expected 13:1 diastereomeric ratio in favor of the 1,2- syn -thioaminal. This reaction pathway is similar to that previously reported for substitutions of C2-alkoxy dithioacetals . It should be noted that all of the different low-energy C1–C2 and C2–C3 conformations were examined at the ground state and transition state levels.…”

“…A model substrate was examined to determine the stereoselective outcome of nucleobase additions to dithioacetals with a C2-stereogenic center containing a fluoride atom. Our proposed mechanism for this substitution first involves the activation of a dithioacetal ( 5 ) with a halogen (X 2 ) to generate interconverting halothioether intermediates ( 6a and 6b ) that subsequently react with the silylated nucleobase to generate 1,2- syn - and 1,2- anti -thioaminals 7a and 7b (Scheme ). If the substitution steps ( k 2 and k 3 ) are significantly slower than the epimerization ( k 1 ), the stereochemical outcome of the substitution reaction is dependent on the difference in free energy between the preferred transition states leading to the 1,2- syn and 1,2- anti products, as stated by the Curtin–Hammett principle. , …”

Synthesis of nucleoside analogues using acyclic diastereoselective reactions

“…At this point in the strategy, we made use of our novel two-step acyclic approach for the synthesis of nucleoside analogues, 40 the mechanism of which has been examined in detail using DFT calculations. 8,41 We have recently reported the use of this strategy with a C3-quaternary center and a fluoride at C2, 8 however, this is the first report of using this strategy with a thioaminal bearing a C2-hydroxy and a C3-quaternary center. An essential aspect of this strategy is the diastereoselective synthesis of a 1,2-syn thioaminal (29) from a dithioacetal (4).…”

“…The presence of the counteranion (I -) stabilizes this transition state and prefers to be located on the opposite side of the incoming nucleobase. 8,41 Selective removal of the less hindered C4-TBS protecting group provided the necessary thioaminals 30 and 31 in excellent yields. The next key step of our acyclic approach involves a stereospecific displacement of the activated sulfur of the thioaminal by the C4-hydroxy with inversion of configuration (O4'-C1 cyclization).…”

Using Neighboring-Group Participation for Acyclic Stereocontrol in Diastereoselective Substitution Reactions of Acetals

“…Neighboring-group participation is a widely used approach to control stereochemistry in substitution reactions of carbohydrate compounds. − Most commonly, acyloxy groups, namely, the acetate, benzoate, and pivaloate esters, ,, are used to favor the 1,2- trans products with high selectivity. ,, Neighboring-group participation has not emerged as a useful approach for controlling stereochemistry in reactions involving acyclic acetals, however. − The use of neighboring-group participation to control stereochemistry in acyclic systems, as illustrated in eq , would be significant because it would provide access to the products expected from nucleophilic additions to α-alkoxy aldehydes that would be governed by the Felkin–Anh or related − stereochemical models. Such transformations, however, often give products with modest diastereoselectivity. ,,− …”