Formation of α-chiral centers by asymmetric β-C(sp3)-H arylation, alkenylation, and alkynylation

Abstract

The enzymatic β-C-H hydroxylation of the feedstock chemical isobutyric acid has enabled the asymmetric synthesis of a wide variety of polyketides. The analogous transition metal-catalyzed enantioselective β-C-H functionalization of isobutyric acid-derived substrates should provide a versatile method for constructing useful building blocks with enantioenriched α-chiral centers from this abundant C-4 skeleton. However, the desymmetrization of ubiquitous isopropyl moieties by organometallic catalysts has remained an unanswered challenge. Herein, we report the design of chiral mono-protected aminomethyl oxazoline ligands that enable desymmetrization of isopropyl groups via palladium insertion into the C(sp³)-H bonds of one of the prochiral methyl groups. We detail the enantioselective β-arylation, -alkenylation, and -alkynylation of isobutyric acid/2-aminoisobutyric acid derivatives, which may serve as a platform for the construction of α-chiral centers.

Fig. 1. Construction of α-chiral centers via C–H activation

(A) Enzymatic approach. (B) Organometallic approach. (C) Challenges in chiral differentiation. DG, directing group; Me, methyl group; t-Bu, tert-butyl group; CoA, Coenzyme A; R, alkyl or aryl group; pin, pinacolato group.

Fig. 2. Enantioselective C–H arylation of isobutyric acid and 2-aminoisobutyric acid

(A) Ligand optimization. (B) Arylation of isobutyric acid. (C) Arylation of 2-aminoisobutyric acid. For each entry number (in boldface), data are reported as isolated yield. See supplementary materials for experimental details. ^*10 mol% Pd(OAc)₂, 20 mol% L30, Ar-I, Ag₂CO₃, toluene, 50 °C, 72 h. ArF, 4-(CF₃)C₆F₄; p-Tol-I, para-tolyl iodide; equiv., equivalent; Et, ethyl group; Ph, phenyl group; Ac, acetyl group; Ar(Het), (hetero)aryl group; TBS, fert-butyldimethylsilyl group; Bn, benzyl group; Boc, tert-butyloxycarbonyl group; Ts, tosyl group; Phth, phthalimido group; HFIP, hexafluoro-2-propanol.

Fig. 3. Enantioselective C–H alkenylation and alkynylation of isobutyric acid

For each entry number (in boldface), data are reported as isolated yield. See supplementary materials for experimental details. ^*10 mol% Pd(MeCN)₂Ch₂ was used instead of Pd(OAc)₂. NaOAc was used as the additive. TIPS, triisopropylsilyl group.

Fig. 4. Diverse functionalizations of the remaining methyl group

For each entry number (in boldface), data are reported as isolated yield. See supplementary materials for experimental details. Reagents and conditions: (a) 10 mol% Cu(OAc)₂, NHEtPh, Ag₂CO₃, toluene, 100 °C (b) H₂O₂, aq. buffer (pH = 7), THF, rt.