Stereoselective Formation of Quaternary Carbon Centers: Alkylation ofα,α-Disubstituted Amide Enolates

Abstract

The stereoselective formation of quaternary carbon centers is one of the most challenging tasks in organic chemistry and can only be achieved using methods which employ some form of carbon ± carbon bond forming reaction. [1] One of the most straightforward methods for the formation of carbon ± carbon bonds is the alkylation of an enolate with an alkyl halide and, fluoride ions were 1 to 2 mm. The protonation constant of fluoride in water is: log K HF/F 3.15. NMR Measurements: 1 H NMR spectra were recorded on a Bruker AM500 spectrometer at 500 MHz. Binding constants were obtained by NMR titrations of L with fluoride from 25 measurements in D 2 O at pD 5.0 AE 0.1. Initial concentrations were [L] 0 2 mm and titrations were performed using aliquots from a 20 mm stock solution of NaF. A solution of the sodium salt of [2,2,3,3-D 4 ]-3-(trimethylsilyl)propionic acid (TPS) in D 2 O in a capillary tube was used as an external reference. The pD value was adjusted with a concentrated solution of TsOH and NaOD in D 2 O. All spectra were recorded at room temperature. The association constants K s were calculated by fitting f to d obs (consisting of several independent NMR signals) with a 1:1 association model using Sigma Plot software. Equations (1) and (2) were used, where L is the ligand and A À is the anion, and the error limit in K is less than 10 %:The Job×s plot was performed by examining different concentration ratios of L and NaF in D 2 O at pD 5.0 AE 0.1, while maintaining the total concentration of the ligand plus NaF at 10 mm. The pD value was adjusted with a concentrated solution of TsOH and NaOD in D 2 O. NMR measurements were recorded at room temperature.

Chiral Auxiliary Based Reductive Alkylation of α,α‐Diallkyl β‐Phosphonyl Esters

“…We therefore assume that the formation of the enolates from the C-P bond cleavage might occur through an intermediary carboanion rather than in a concerted mechanism that is proposed for the thioglycolate lactams (Scheme I). 6 Finally, the reaction of 2h with EtI also proceeded smoothly to give 3h in 82:18 dr (R/S). 13,17,18 In summary, we have demonstrated that the acyclic b-phosphonyl esters underwent the reductive alkylation as facilely as previously reported cyclic precursors.…”

“…In 2002, Gleason et al reported an elegant ap-proach for the asymmetric formation of quaternary carbon centers by the reductive alkylation of chiral bicyclic thioglycolate lactams. 6 This method was based on the stereospecific generation of tetrasubstituted enolates through the lithium butyldiphenylide (LiDBB)-induced reductive cleavage of C-S bond, with the geometry of the resulting enolates (E/Z) being strictly defined by the constrained S-C-C-O dihedral angle as well as relative locations of two pre-introduced alkyl groups. The diastereofacial selectivity of the subsequent alkylation was then controlled by the liberated chiral auxiliary to lead to the products with high diastereomeric excesses (Scheme I).…”

Reductive Lithiation and Multilithiated Compounds in Synthesis

“…A judicious choice of the alkyl substituents (R 1 vs R 2 ) within the whole reaction sequence allowed the recovery of enantiomeric products, as demonstrated by a comparison of results obtained with R 1 = n-Pr and R 2 = n-Bu (recovery of (R)-21, 96% ee) versus R 1 = n-Bu and R 2 = n-Pr (recovery of (S)-21, 95% ee) (Scheme 12.6) [23].…”

Enantioselective synthesis of all-carbon quaternary stereogenic centers in acyclic systems

“…This selectivity enhancement presumably has its origin in the low alkylation selectivity of the minor E-enolates. 65 Finally, enantiomeric pairs of molecules may be formed simply by inverting the order of alkylation followed by cleavage of the chiral auxiliary (Scheme 46). Branched alkyl halides such as isobutyl iodide were slower to react, but gave acceptable yields at À78 1C in the presence of HMPA.…”