Enantioselective Synthesis of Chiral α-Azido and α-Aryloxy Quaternary Stereogenic Centers via the Phase-Transfer-Catalyzed α-Alkylation of α-Bromomalonates, Followed by S_N2 Substitution

Abstract

A new efficient synthetic method for chiral α-azido-α-alkylmalonates and α-aryloxy-α-alkylmalonates was developed. The enantioselective α-alkylation of diphenylmethyl tert-butyl α-bromomalonate under phase-transfer catalytic conditions [(S,S)-3,4,5-trifluorophenyl-NAS bromide, 50% KOH, toluene, and -40 °C) provided the corresponding α-bromo-α-alkylmalonates in high chemical yields (≤98%) and high optical yields (≤99% ee). The resulting α-alkylated products were converted to α-azido-α-alkylmalonates (≤96%, ≤97% ee) and α-aryloxy-α-alkylmalonates (≤79%, ≤93% ee) by S2 substitution with sodium azide and aryloxides, respectively.

An enantioconvergent halogenophilic nucleophilic substitution (S N 2X) reaction

“…Organic azides act as valuable building blocks in synthetic chemistry, but the preparation of chiral tertiary azides remains nontrivial. Two examples of the formation of chiral tertiary azides were reported via S N 2 substitution, but these reactions required the use of enantiopure tertiary halide precursors (16,17). After extensive investigations, we discovered that 3 mol % of PN5 and 2.0 equivalents of NaN 3 , in the presence of a two-phase mixture of diisopropyl ether (iPr 2 O, 1.0 ml) and saturated K 2 CO 3 aqueous solution (0.2 ml), were found to be essential for the enantioconvergent transformation of bulky activated tertiary bromide 6a to tertiary azide 7a smoothly over 3 to 4 days at low temperature (−40°C) with good yield (86%) and ee (94%) ( Fig.…”

Kinetic and Dynamic Kinetic Resolution of Racemic Tertiary Bromides by Pentanidium‐Catalyzed Phase‐Transfer Azidation

“…We found that the absence of water is crucial to obtain a high selectivity factor ( s ). There are few synthetic strategies to access highly enantiopure tertiary bromides . However, new experimental observations and DFT modeling led us to propose that the enantioconvergent azidation of tertiary bromides proceeded through dynamic kinetic resolution (DKR).…”

Chiral phase-transfer catalysis in the asymmetric α-heterofunctionalization of prochiral nucleophiles

“…On the one hand the hereby accessed products can be of significant interest with respect to biological or medical applications, which is especially the case for α-fluoro targets [ 64 – 65 ]. On the other hand, such α-halo carbonyl compounds may serve as valuable intermediates for further manipulations like, for example, enantiospecific nucleophilic displacement reactions [ 66 – 67 ].…”