Mechanistic Insight into Asymmetric Hetero-Michael Addition of α,β-Unsaturated Carboxylic Acids Catalyzed by Multifunctional Thioureas

Abstract

Carboxylic acids and their corresponding carboxylate anions are generally utilized as Brønsted acids/bases and oxygen nucleophiles in organic synthesis. However, a few asymmetric reactions have used carboxylic acids as electrophiles. Although chiral thioureas bearing both arylboronic acid and tertiary amine were found to promote the aza-Michael addition of BnONH to α,β-unsaturated carboxylic acids with moderate to good enantioselectivities, the reaction mechanism remains to be clarified. Detailed investigation of the reaction using spectroscopic analysis and kinetic studies identified tetrahedral borate complexes, comprising two carboxylate anions, as reaction intermediates. We realized a dramatic improvement in product enantioselectivity with the addition of 1 equiv of benzoic acid. In this aza-Michael reaction, the boronic acid not only activates the carboxylate ligand as a Lewis acid, together with the thiourea NH-protons, but also functions as a Brønsted base through a benzoyloxy anion to activate the nucleophile. Moreover, molecular sieves were found to play an important role in generating the ternary borate complexes, which were crucial for obtaining high enantioselectivity as demonstrated by DFT calculations. We also designed a new thiourea catalyst for the intramolecular oxa-Michael addition to suppress another catalytic pathway via a binary borate complex using steric hindrance between the catalyst and substrate. Finally, to demonstrate the synthetic versatility of both hetero-Michael additions, we used them to accomplish the asymmetric synthesis of key intermediates in pharmaceutically important molecules, including sitagliptin and α-tocopherol.

Carboxylation of Alkenyl Boronic Acids and Alkenyl Boronic Acid Pinacol Esters with CO2 Catalyzed by Cuprous Halide

“…1 H NMR (400 MHz, [D 6 ]DMSO) δ = 12.35 (s, 1H), 7.42 (d, J = 7.2 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.24 (t, J = 7.3 Hz, 1H), 6.50 (d, J = 16.0 Hz, 1H), 6.31 (dt, J = 16.0, 7.1 Hz, 1H), 3.20 (dd, J = 7.1, 1.4 Hz, 2H). 13 C NMR (101 MHz, [D 6 ]DMSO) 13 C NMR (101 MHz, [D 6 ]DMSO) δ = 173.13, 137.18, 132.70, 129.10, 127.87, 126.49, 123.66, 38.30 …”

Emerging unconventional organic solvents for C–H bond and related functionalization reactions

“…Recently for example, Papai and Takemoto reported an asymmetric hetero-Michael addition of a,b-unsaturated carboxylic acids under organo-catalytic conditions (N-H bond functionalization, Scheme 13). 35 Some of the best results in terms of conversion and especially enantiomeric excess were obtained in C 2 Cl 4 as a solvent. The highly halogenated character of the solvent possibly imposes a good compromise between dissolving capacity and maximized H-bonding strength/efficiency between substrates and supramolecular chiral catalyst -thus a very different mode of action than that of for example HFIP.…”

Highly Enantioselective Synthesis of Sitagliptin

“…[7] This was achieved using ruthenium and (R)-DM-SEGPHOS as ligand (scheme 1, B). Apart from above asymmetric reduction routes, sitagliptin is prepared using, traditional chiral auxiliary based organic synthesis, [8] chiral ammonia equivalents, [9,10] allylic amination, [11] enolate alkylation, [12] enzymatic synthesis [13] and organocatalytic synthesis. [14] Even a continuous manufacturing process using microreactors has been recently developed for the synthesis of sitagliptin.…”