Observation of Hyperpositive Non-Linear Effect in Asymmetric Organozinc Alkylation in Presence of N-Pyrrolidinyl Norephedrine

Abstract

Phenomena related to asymmetric amplification are considered to be key to understanding the emergence of homochirality in life. In asymmetric catalysis, theoretical and experimental models have been studied to understand such chiral amplification, in particular based on non-linear effects. Three decades after the theoretical demonstration that a chiral catalyst, when not enantiopure, could be more enantioselective than its enantiopure counterpart, we show here a new experimental example of nonlinear hyperpositive effect. We report here our investigations in the enantioselective zinc-catalyzed alkylation of benzaldehyde with N-pyrrolidinyl norephedrine as partially resolved chiral ligand, which shows a significant hyperpositive non-linear effect. A study of the underlying mechanism was conducted, which allows us to confirm a mechanism that implies a monomeric and a dimeric complex both catalyzing the reaction at a steady state and giving different enantioselectivities.

Mechanistic Applications of Nonlinear Effects in First‐Row Transition‐Metal Catalytic Systems

“…The catalytic system of N ‐pyrroalkyl normethephedrine (NPNE) ligand also follows the mono‐ dimer competition model, and there was a hyperpositive NLE in this system. [ 76 ]…”

Catalyst or Catalyst System? Nonlinear Behaviour and the Limits of Mechanistic Understanding in Proline-Based Asymmetric Catalysis.

“…Chiral ligands derived from proline are numerous and have demonstrated their usefulness in many enantioselective catalytic reactions, with or without metal. [17] Its scaffold (core structure) classifies this family as "privileged chiral catalysts", which prompted us to investigate whether these ligands show systems-level behaviour similar to their counterparts based on ephedrine [12][13][14][15][16] or camphor [18,19] in the zinc-catalysed alkylation of benzaldehyde. The reaction starts with the chiral aminoalcohol ligand reacting with a first equivalent of dialkylzinc, forming a ligand-alkylzinc complex that can activate benzaldehyde and another equivalent of dialkylzinc to give a chiral alkylzinc-alkoxide product.…”

“…[20,21] The ligand-alkylzinc complex can also aggregate, giving rise to additional catalytic species in some cases. [12][13][14][15][16] We chose diphenyl-N-methyl-prolinol DPMP (1), diphenylprolinol DPP (2) and 5-(hydroxydiphenylmethyl)-2-pyrrolidinone DPPy (3) as chiral ligands for our study, which are all derived from proline and differ only by small chemical modifications. [20] DPMP ligand (1) Figure 2a displays the correlation between the enantiomeric excess of the product (eeP) and the enantiomeric excess of the ligand (eeL) for the asymmetric addition of diethylzinc to benzaldehyde in presence of 1, an Nmethylated prolinol ligand (the S-configuration being the major enantiomer in all ligand studies).…”

“…The 2 system consists not of one but at least two non-racemic catalytic species yielding product of opposite signs. Taken together with the NMR data and the precedent of ephedrine-based ligands, [12][13][14][15][16] one could be tempted to conclude on a monomer-dimer system (cf. Fig.…”

“…Recently we have established the importance of catalyst loading-dependent eeP screening as a probe for multiple aggregation levels that are catalytically active at the same time. [12][13][14][15][16] This has led to an understanding of more complex NLEs, such as hyperpositive and enantiodivergent NLEs, which include a coexistence of active monomeric and active dimeric species. A higher degree of complexity seems attainable if one considers that higher levels of aggregation could be envisaged, such as a monomer-dimer-trimer system level as displayed in Fig.…”