Deciphering Stereoselectivity in Hurd-Claisen Rearrangements: A Comprehensive Study of Electrostatic Interactions from Shubin's Energy Decomposition Analysis.

In this study, we explore the stereoselectivity of Hurd-Claisen Rearrangements, focusing on the influence of two electron-withdrawing groups and eight diverse substituents. Utilizing the Curtin-Hammett principle, we performed energy calculations for reactions, products, and transition states using the M062X/def2TZVPP compound model. Our analysis reveals that kinetic factors predominantly dictate the reaction equilibrium. A key aspect of our research is the application of Shubin's energy decomposition analysis to optimized transition states, highlighting the significant role of electrostatic interactions in determining stereoselectivity. We further dissected each transition state into four fragments: the electron-withdrawing groups ( C O 2 E t ${CO_2 Et}$ , C N ${CN}$ ), the Hurd group ( H ${H}$ ), various substituents ( C H 3 ${CH_3 }$ , E t ${Et}$ , S P r o p ${SProp}$ , T B u t ${TBut}$ , I s o B u t ${IsoBut}$ , N H 2 P h ${NH_2 Ph}$ , N O 2 P h ${NO_2 Ph}$ , P h ${Ph}$ ), and the central fragment. This fragmentation approach enabled an in-depth analysis of group dipole moments, providing insights into the electrostatic forces at play. Our findings shed light on the intricate mechanisms driving stereoselectivity in Hurd-Claisen Rearrangements and enhance the understanding of molecular interactions, offering valuable implications for organic synthesis.

Electrochemical Reactors Enable Divergent Site Selectivity in the C-H Carboxylation of N-Heteroarenes.

Catalytic and switchable C-H functionalization of N-heteroarenes under easily tunable conditions is a robust but challenging tool for the construction of biologically relevant compounds. Recently, a general electrochemical strategy has been developed for the direct C-H carboxylation of N-heteroarenes with CO2 , and by simply choosing different types of cell setups, carboxylated products are furnished with excellent and tunable site selectivity. This study also paves the way for regulating the reactivity modes in electrochemical synthesis.

On the Mechanism of the Asymmetric Aldol Addition of Chiral N-Amino Cyclic Carbamate Hydrazones: Evidence of Non-Curtin-Hammett Behavior.

he mechanistic details of the aldol addition of N-amino cyclic carbamate (ACC) hydrazones is provided herein from both an experimental and computational perspective. When the transformation is carried out at room temperature the anti-aldol product is formed exclusively. Under these conditions the anti- and syn-aldolate intermediates are in equilibrium and the transformation is under thermodynamic control. The anti-aldolate that leads to the anti-aldol product was calculated to be 3.7 kcal mol-1 lower in energy at room temperature than that leading to the syn-aldol product, which sufficiently accounts for the exclusive formation of the anti-aldol product. When the reaction is conducted at -78 °C it is under kinetic control and favors formation of the syn-aldol addition product. In this case, it was found that a solvent separated aza-enolate anion and aldehyde form a σ-intermediate in which the lithium cation is coordinated to the aldehyde. The σ-intermediate collapses with a very small activation barrier to form the ß-alkoxy hydrazone intermediate. The chiral nonracemic lithium aza-enolate discriminates between the two diastereotopic faces of the pro-chiral aldehyde, and there is no rapid direct pathway that interconverts the two diastereomeric intermediates. Consequently, the reaction does not follow the Curtin-Hammett principle and the stereochemical outcome at low temperature instead depends on the relative energies of the two σ-intermediates.

Asymmetric Synthesis of Cα-Substituted Prolines through Curtin-Hammett-Controlled Diastereoselective N-Alkylation.

Asymmetric synthesis of α-substituted proline derivatives has been accomplished by an efficient chirality-transfer method. High diastereoselectivity of the N-alkylation of the proline ester (C→N chirality transfer) was achieved when a 2,3-disubstituted benzyl group was used as the N-substituent. DFT calculations provided a mechanistic rationale for the high degree of stereoselectivity. The generated N-chirality of the quaternary ammonium salt was transferred back to the α-carbon through a stereoselective [2,3]-Stevens rearrangement (N→C chirality transfer) to give α-substituted proline ester.

Enantiodivergent Hydroboration Reactions of a Racemic Allenylsilane with Diisopinocampheylborane and Curtin-Hammett Controlled Double Asymmetric Crotylboration Reactions of (S)-E-α-phenyldimethylsilyl( d diisopinocampheyl)-crotylborane.

The enantiodivergent hydroboration reactions of racemic allenylsilane (±)-4 with ( d Ipc)2BH and subsequent crotylboration of achiral aldehydes with the product crotylborane (S)-E-5 at -78 °C provide (E)-δ-silyl-anti-homoallylic alcohols 6 in 71-89% yield and with 93-96% ee. Intriguingly, mismatched double asymmetric crotylboration reactions of enantioenriched chiral aldehydes 20 with (S)-E-5 proceed under Curtin-Hammett control to give anti-3-hydroxylcrotylsilanes 24 as the only products.

Enantiodivergent hydroboration reactions of a racemic allenylsilane with diisopinocampheylborane and Curtin-Hammett controlled double asymmetric crotylboration reactions of (S)-E-αphenyldimethylsilyl( d diisopinocampheyl)-crotylborane.

The enantiodivergent hydroboration reactions of racemic allenylsilane (±)-4 with ( d Ipc)2BH and subsequent crotylboration of achiral aldehydes with the product crotylborane (S)-E-5 at -78 °C provide (E)-δ-silyl-anti-homoallylic alcohols 6 in 71-89% yield and with 93-96% ee. Intriguingly, mismatched double asymmetric crotylboration reactions of enantioenriched chiral aldehydes 20 with (S)-E-5 proceed under Curtin-Hammett control to give anti-ß-hydroxylcrotylsilanes 24 as the only products.

Oxa- and Azabenzonorbornadienes as Electrophilic Partners under Photoredox/Nickel Dual Catalysis.

Herein, the introduction of oxa- and azabenzonorbornadienes into photoredox/nickel dual catalysis in a regioselective and diastereoselective transformation is disclosed. The inherent advantages of this dual catalytic system allow the use of alkyl motifs forming exclusively cis-1,2-dihydro-1-naphthyl alcohol backbones using readily accessible 4-alkyl-1,4-dihydropyridines (DHPs). Whereas previous studies have emphasized the use of nucleophilic organometallic coupling partners, this protocol grants access to a rather unexplored core featuring alkyl residues, while avoiding the use of highly reactive organometallic species (i.e., M = Al, Mg, Li, Zn, Zr). DFT calculations support a oxidative addition/reductive elimination mechanism, followed by a Curtin-Hammett scenario that controls the regioselectivity of the process, unlike previously reported transformations that proceed via a carbometalation/ ß-oxygen elimination mechanism.