Cobalt–Bisoxazoline-Catalyzed Asymmetric Kumada Cross-Coupling of Racemic α-Bromo Esters with Aryl Grignard Reagents

Abstract

The first cobalt-catalyzed asymmetric Kumada cross-coupling with high enantioselectivity has been developed. The reaction affords a unique strategy for the enantioselective arylation of α-bromo esters catalyzed by a cobalt-bisoxazoline complex. A variety of chiral α-arylalkanoic esters were prepared in excellent enantioselectivity and yield (up to 97% ee and 96% yield). The arylated products were transformed into α-arylcarboxylic acids and primary alcohols without erosion of ee. The new enantioenriched α-arylpropionic esters synthesized herein are potentially useful in the development of nonsteroidal anti-inflammatory drugs. This method was conducted on gram-scale and applied to the synthesis of highly enantioenriched (S)-fenoprofen and (S)-ar-turmerone.

Nickel/Photoredox‐Catalyzed Asymmetric Reductive Cross‐Coupling of Racemic α‐Chloro Esters with Aryl Iodides

“…We were pleased to find that not only primary alkyl groups, such as Et ( 4 a ), n ‐Bu ( 4 b ), and i Bu ( 4 c ), but also secondary alkyl groups, including isopropyl ( 4 d ) and cyclopentyl ( 4 e ), exhibited good yields (77–82 %) and excellent enantioselectivities (91–94 %). In prior publications, secondary alkyl esters either gave low enantioselectivities or were not included among the reported substrates . Alkyl groups bearing aryl substituents ( 4 f – 4 i ) were also tolerated and the corresponding coupling products were isolated in 58–83 % yield with enantioselectivities of 87–89 %.…”

“…Herein, we employ an organic photoredox catalyst with Hantzsch ester (HEH) as the terminal organic reductant to realize the nickel catalyzed asymmetric reductive cross‐coupling of α‐chloro esters with aryl iodides to furnish α‐aryl esters (Scheme D). This method represents an advance over prior methods that employed prefunctionalized aryl coupling partners (organosilane, Grignard, or organozinc reagents), or preformed enolates . It is also an alternative strategy for the enantioselective formation of C(sp 2 )−C(sp 3 ) bonds to the use of stoichiometric metal as reductant.…”

Asymmetric cross-coupling of racemic α-bromo esters with aryl Grignard reagents catalyzed by cyclopropane-based bisoxazolines cobalt complexes

“…The temperature and solvent were optimized in our cobalt-catalyzed asymmetric Kumada cross-coupling, 9 and the p-isobutylphenyl Grignard reagent was prepared from 4-isobutylphenyl bromide and magnesium turnings. 18 The phenyl-substituted bisoxazoline 1c exhibited the best enantioselectivity (83:17 er, entry 3), and other ligands with isopropyl, tert-butyl and benzyl gave moderate enantioselectivities (76:24-81:19, entries 1, 2 and 4).…”

“…3,4 However, the relatively poor functional group compatibility of Grignard reagents has limited their utility in asymmetric catalysis. 5,6 Only a few asymmetric versions of this reaction are impressive and highly enantioselective to date, 2,7-9 including nickel-ferrocenylphosphine catalyzed asymmetric biaryl coupling by Ito and Hayashi et al; 7 nickel-bisoxazoline catalyzed cross-coupling of racemic a-bromoketones with aryl Grignard reagents by Fu et al; 8 cobalt-bisoxazoline catalyzed cross-coupling of racemic a-bromoesters with aryl Grignard reagents by us, 9 and iron-bisphosphine catalyzed cross-coupling of racemic a-chloroesters with aryl Grignard reagents by Nakamura et al 2 The asymmetric Kumada cross-coupling, therefore, is still in its infancy and remains an important synthetic challenge.…”

Chiral Brønsted Acid Catalyzed Enantioconvergent Propargylic Substitution Reaction of Racemic Secondary Propargylic Alcohols with Thiols

“…[2] However, the reactiona tt he chiral sp 3 -hybridized carbon atom of ar acemic electrophile has not been largelye xplored because of the chiral information of the racemic elec-trophile. [3][4][5] Amongt he reported approaches,t he opticalk inetic resolution of the racemic electrophile through an S N 2r eaction has been established using ac hiral catalyst. [6] Considering the ideal production of the desired enantioenricheds ubstitution product in 100 %t heoretical yield, namely,a ne nantioconvergent process, the elimination of the initial chiral information that originated from the racemic electrophile should be realized.…”