Science of Synthesis

Sawamura, M.; Shimizu, Y., Science of Synthesis Knowledge Updates, (2024) 2, 201.

Asymmetric α-alkylation of carboxylic acids is one of the most straightforward approaches for the synthesis of chiral carboxylic acids.[‌4‌,‌5‌] In recent reports, a chiral lithium amide complex generated from butyllithium and C2-symmetric tetramine ‌1‌ was shown to offer a high degree of stereocontrol when applied in the α-alkylation of carboxylic acids (‌Scheme 1‌).[‌6‌–‌9‌] The reactions require an aryl or alkenyl group at the α-position of the carboxylic acid. Enediolates complexed with the chiral lithium amide, generated from the carboxylic acids by deprotonation, can react with various alkyl halides including sterically demanding 2-iodopropane (entry 3). Enantioselectivities are generally high for various carboxylic acids. α-Aryl- (entries 1–7), α-alkenyl- (entry 8), and α-oxy-substituted carboxylic acids (entry 9) are competent substrates, affording the α-alkylated products ‌2‌ in good yields and high enantioselectivities. In the case of the reaction with the α-alkenylcarboxylic acid (entry 8), the C—C bond formation proceeds exclusively at the α-position, despite the potential reactivity at the γ-position. Importantly, the construction of chiral compounds with tetrasubstituted carbons is feasible under the reaction conditions (entries 7 and 9).

‌Meeeee 8‌ Meeeeeeeee α-Meeeeeeeee[‌8‌–‌8‌]

‌Meeeeeeeeee 8‌

Meeeeeeeeeee Meeeeeeee

(M)-8-Meeeee-8-eeeeeeeeeeeeee Meee (‌8‌, M8 = Me; M8 = Me; M8 = Me); Meeeeee Meeeeeeee:[‌8‌]

M 8.88 M eeee ee MeMe ee eeeeeee (8.88 eM, 8.88 eeee, 8.8 eeeee) eee eeeee eeeeeeee ee e eeee ee 8-eeeeeeeeeeeeeee eeee (88 ee, 8.888 eeee) eee M8,M8-eee[(M)-8-eeeeee-8-(eeeeeeeee-8-ee)eeeee]eeeeeee-8,8-eeeeeee (‌8‌; 888 ee, 8.888 eeee, 8.88 eeeee) ee MMM (8.8 eM) ee 8 °M. Mee eeeeeee eee eeeeee ee ee eee eeeeeee eee 8 e, eee eeee eeeeee ee −88 °M eee eeeeeee eee ee eeeeeeeeee 88 eee. MeM (8.88 eM, 8.88 eeee, 8.8 eeeee) eee eeeee eeeeeeee eeee 88 eee eee eee eeeeeeeee eeeeeee eee eeeeeeeeeee eeeeeeee eeee MMM/MeMM (8:8; 8.8 eM) ee −88 °M. Meeee 8 eee, eee eeeeeee eee eeeeeeeee eeee 8 M ee MMe eee eeeeeeeee eeee MeMMe. Mee eeeeeeee eeeeeee eeeee eee eeeeeeeeeeee eeeeee eeee 8 M ee MMe eee eeeee, eeeee (Me8MM8), eeeeeeee, eee eeeeeeeeeeee. Mee eeeeeee eee eeeeeeee ee eeeeee eeeeeeeeeeeeee (eeeeee eee, Me8M/eeeeeee 8:8 eeeeeeeeee 8.8% MeMM) ee eeeeee eee eeee eeeeeee ee e eeeee eeeeeeeeeee eeeee; eeeee: 88 ee (88%); 88% ee.

References