Intermolecular Noncovalent Hydroxy-Directed Enantioselective Heck Desymmetrization of Cyclopentenol: Computationally Driven Synthesis of Highly Functionalized cis-4-Arylcyclopentenol Scaffolds

Abstract

New computationally driven protocols for the Heck desymmetrization of 3-cyclopenten-1-ol with aryldiazonium tetrafluoroborates were developed. These new conditions furnished remarkable product selectivity originating from a resident hydroxyl group and the critical choice of the reaction solvent. Mechanistic insights gleaned from theoretical calculations of the putative transition states predicted toluene as an adequate solvent choice to attain high enantioselectivity by strengthening the noncovalent interaction of the substrate hydroxyl group and the chiral cationic palladium catalyst. Laboratory experiments validated the theoretical predictions, and by employing 2% MeOH/toluene as solvent, the Heck-Matsuda reaction provided exclusively the cis-4-arylcyclopentenols 3a-l in good to excellent yields in enantiomeric excesses up to 99%. The performance of the new PyOx ligand (S)-4-tert-butyl-2-(3,5-dichloropyridin-2-yl)-4,5-dihydrooxazole was also successfully evaluated in the Heck-Matsuda desymmetrization of 3-cyclopenten-1-ol. The synthetic potential of these highly functionalized cis-4-arylcyclopentenols is illustrated by a gold-catalyzed synthesis of cyclopenta[b]benzofuran skeletons.

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

“…To get further insights about these challenging Heck‐Matsuda arylations, we also decided to investigate the enantioselectivity of these reactions through DFT studies. The analysis of the aryl palladium migratory insertion into the alkene has shown to be crucial to rationalize the stereochemical outcome of the Heck reactions on many occasions . Our investigation took into account the four permutations between the orientations of different substrate components for both ( Z )‐ 1 a and ( E )‐ 1 a (Scheme ).…”

“…The analysis of the aryl palladium migratory insertion into the alkene has shown to be crucial to rationalize the stereochemical outcome of the Heck reactions on many occasions. [14,[27][28][29][50][51][52] Our FULL PAPER asc.wiley-vch.de investigation took into account the four permutations between the orientations of different substrate components for both (Z)-1 a and (E)-1 a (Scheme 7). Therefore, we investigated the enantioselectivity of the reaction (i. e.: arylation at either the Re or Si face of a given alkene carbon), and the relative orientation of the ligands during the migratory insertion (i. e.: alkene cis or trans to the oxazoline at the stage of the corresponding σ-arylpalladium).…”

“…[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.…”

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

“…To understand the factors that govern the stereochemical outcome of these reactions, we performed DFT calculations for a variety of transition states (TSs) usually invoked in the mechanistic rationale . Key to this transformation is the migratory insertion TS, which is generally treated as an irreversible step with prior rapid equilibration of intermediates (Curtin–Hammett scenario) .…”

Noncovalent Substrate‐Directed Enantioselective Heck Reactions: Synthesis of S‐ and P‐Stereogenic Heterocycles

“…Recently,w er eported on hydroxyl-group-directed asymmetric Heck-Matsudaa rylations associatedw ith ad esymmetrization strategy. [17] According to our rationalea nd computational studies, the cationic aryl-palladiumi ntermediate binds the hydroxyl-group-containing substrate in am anner that favors an oncovalent interaction between the cationic palladium and the hydroxyl group. Contraryt oo ther transition-metal substrate-directable reactions, [18] the directingh ydroxy group is located outside the coordinating sphere of palladium.…”