Stereoselection Parameters and Theoretical Model in the Enantioselective Protonation of Enolates with α-Sulfinyl Alcohols

Abstract

The effects of the solvent, temperature, presence of lithium salts in the medium, and acidity of the proton source on enantioselective protonation with R-sulfinyl alcohols 2a-e were studied. Stereoselectivity was generally enhanced when lithium bromide was present in the medium during enolization and also with the use of methylene chloride solutions. Conversely, the optimal reaction temperature varied with the R-sulfinyl alcohol used as a proton source, and its effect appears to be related to both the acidity of the proton source and the enolate structure. R-Sulfinyl alcohols 2a and 2b gave the best results when the reactions were carried out at -100°C, while the optimal temperature with 2c was -78°C. The same ee values were obtained with 2d and 2e at either -100 or -78°C. In addition, an efficient synthesis of R-sulfinyl alcohols 2b and 2c is described.

Recent developments in chiral non-racemic sulfinyl group chemistry in asymmetric synthesis

“…Stereoselectivity is generally enhanced when lithium bromide is present in the medium during enolisation and when the reaction is performed in methylene chloride. 207 Furthermore, optimum enantioselective protonation of 2-alkylcycloalkanones is reached when the α-sulfinyl alcohol/enolate ratio is 3:1. 208 This ratio can be lowered to 1/1 if an achiral proton source such as trifluormethanol is present in the medium to regenerate the α-sulfinyl alcohol.…”

From overstoichiometric to substoichiometric enantioselective protonation with 2-sulfinyl alcohols: A view in perspective

“…On the other hand, sulfinyl alcohols 1a-n showed variable efficacy depending on the configuration at the stereogenic carbon atom and the types of substituents bound to this carbon. Sulfinyl alcohols 1a-f in which the alcohol was secondary and which had an (S, Rs) configuration at the stereogenic centers were found to be powerful protonating agents ( Table 2, entries 1-6) 10 For these alcohols, a variation in the substituent bound to the stereogenic carbon only slightly affected the stereoselectivity. On the other hand, with the diastereomeric 2-sulfinyl alcohols (R, Rs)-1g-h, a change in the substituent was associated with noticeable changes in enantioselectivity.…”

“…For the more acidic perfluorinated alcohols 1a-b, a higher enantioselectivity in the protonation of the lithium enolate 4a was achieved when the reaction was carried out at low temperature (Table 3, entries 1 and 3). 10 In contrast, difluorinated alcohol 1c showed unique behavior. Enantioselective protonation at -78 o C over 1.5 h gave the highest e.e.…”

“…Thus, for a given temperature and proton source, stereoselectivity is the complex result of several factors that might reflect the composition of the mixture formed by the enolate as an ion pair, pure-aggregate or mixed-aggregate, and the rate of the assembly of each type of enolate with the proton source. 10,13 The increase in enantioselectivity with an increase in the temperature of protonation observed with alcohols 1c and 1f is not common in the field of enantioselective protonation. In fact, there is only one additional example in the literature concerning the protonation of a silyl enol ether by mandelic acid bound to a polymeric resin.…”

“…We observed this tendency in the reaction of 2-sulfinyl alcohols with lithium ketone enolates. 10 Poor enantioselectivity was achieved when enolate was generated in toluene as a solvent (Table 1, entry 16). The use of dimethyl ether gave better stereoselectivity (Table 1, entry 15).…”