Enantioselective, Noncovalent, Substrate‐Directable Heck–Matsuda and Oxidative Heck Arylations of Unactivated Five‐Membered Carbocyclic Olefins

Abstract

Highly diastereo- and enantioselective, noncovalent, substrate-directable Heck desymmetrizations of cyclopentenyl olefins containing hydroxymethyl and carboxylate functional groups are presented. These conformationally unbiased cyclic olefins underwent effective arylations in yields of up to 97 %, diastereoselectivity up to >20:1, and enantiomeric excesses of up to 99 %. Noncovalent directing effects were shown to be prevalent in both Heck-Matsuda and oxidative Heck reactions, allowing the preferential formation of cis-substituted aryl cyclopentenes containing two stereocenters, including quaternary stereocenters. These results further validate the internal out-of-coordination-sphere ion-dipole interaction concept directing the reaction diastereoselectivity to the cis-Heck product. This approach is complementary to existing methods using bis-phosphine monoxide ligands to give the opposite trans-diastereoisomer. The applicability of the method is showcased by the straightforward synthesis of a potent phosphodiesterase 4 inhibitor in a diastereo- and enantioselective manner. The reaction is operationally simple and has broad scope with regard to the nature of the arenediazonium salt and boronic acid employed. The mechanism and origin of stereoselectivity were investigated with control experiments and DFT calculations that fully supported the stabilizing internal out-of-coordination-sphere ion-dipole interaction between the resident functional group and cationic palladium.

Benign Arylations of Dimethyl Itaconate via Heck–Matsuda Reaction Utilizing in‐Situ Generated Palladium on Aluminum Oxide

“…The Heck–Matsuda reaction, which has provided valuable services in organic synthesis over the past decades, opens up a way out of the limitations of the previous presentation methods described above …”

Catalytic Enantioselective Aminopalladation–Heck Cascade

“…Recent years have witnessed the significant progress in the development of Pd II -catalyzed enantioselective oxidative Heck reaction between arylboronic acids and alkenes. [14][15][16][17][18][19][20] However, the heteroarene-derived boronic acids, with few exceptions, are notably absent in the scope exploration of these reports. In this regard, the successful use of 1-tosyl-1Hindol-3-yl boronic acid as a reaction partner in the asymmetric redox-relay oxidative arylation of alkenols is noteworthy.…”

Enantioselective Heck Arylation of Acyclic Alkenol Aryl Ethers: Synthetic Applications and DFT Investigation of the Stereoselectivity

“…[10,11] Additionally, the introduction of selectivity-inducing strategies, such as the use of redox relay, [12][13][14][15][16][17][18][19][20][21][22][23][24][25] and directing groups have also greatly improved and extended the scope of this reaction. [26][27][28][29][30][31] However, in spite of its tremendous success involving nonactivated and cyclic electron-rich alkenes, the effective arylation of acyclic electron-rich alkenes has been lagging behind significantly. Among the cyclic activated alkenes that can be employed in enantioselective Heck reactions, it includes tetrahydropyrans, dihydrofurans, endocyclic enecarbamates, and enelactams.…”

“…Recent developments in the enantioselective Heck arylations have focused mostly on the use of chiral bisphosphine monoxides (BPMO), P , N ‐ligands, N , N ‐ligands, and phase‐transfer chiral counterions, although the popular bidentate phosphines are still commonplace . Additionally, the introduction of selectivity‐inducing strategies, such as the use of redox relay, and directing groups have also greatly improved and extended the scope of this reaction . However, in spite of its tremendous success involving nonactivated and cyclic electron‐rich alkenes, the effective arylation of acyclic electron‐rich alkenes has been lagging behind significantly.…”