Catalysis of the Hajos—Parrish—Eder—Sauer—Wiechert Reaction by cis‐ and trans‐4,5‐Methanoprolines: Sensitivity of Proline Catalysis to Pyrrolidine Ring Conformation

Abstract

Methanoprolines are found to be catalysts for the Hajos–Parrish–Eder–Sauer–Wiechert reaction.[1] cis‐4,5‐Methanoproline exhibits catalytic ability similar to proline (86% yield, 93% ee), whereas the trans‐4,5‐methanoproline is less selective (67% yield, 83% ee) and shows less acceleration. The reaction was also studied with hybrid density functional theory (B3LYP). The nearly planar cis‐4,5‐methanoproline amine better reflects the planar iminium of the transition states than the pyramidalized trans‐4,5‐methanoproline. This difference in conformation is responsible for the observed higher enantioselectivity and enhanced catalytic behavior of the cis‐4,5‐methanoproline.

Quantum Mechanical Investigations of Organocatalysis: Mechanisms, Reactivities, and Selectivities

“…A later study involving a single point at the B3LYP/6-311+G(2df, p) level of theory was shown to reproduce the exact experimental stereoselectivity of 2.2 kcal/mol for the Hajos-Parrish reaction. 20 …”

“…20 At the time, the Hanessian group had reported the synthesis of cis - and trans -4,5-methanoprolines as conformationally rigid proline surrogates ( 5 and 6 ). Interestingly, the Hanessian group discovered that the cis -4,5-methanoprolines exhibited similar stereoselectivity and reactivity as proline in the Hajos-Parrish reaction, whereas the trans -4,5-methanoproline was a poorer catalyst, both in terms of selectivity and rate.…”

Catalytic properties of 4,5-bridged proline methano- and ethanologues in the Hajos–Parrish intramolecular aldol reaction

“…In previous studies we reported that 4,5-methano-L-prolines were catalytically competent in the Hajos-Parrish reaction. 22 The higher enantioselectivity (93% ee) provided by cis-4,5methano-L-proline 4 compared to the trans-isomer 5 (82% ee) was rationalized based on the conformational preferences of the respective proline derivatives to achieve a transition structure that would favor a planar enamine geometry (vide infra). It was anticipated that the NC 5 methine-H in the trans-congener 5 would be favorably oriented to interact with the developing alkoxide, which in combination with hydrogen bond donation from the carboxylic acid group, would lead to the highly enantioenriched cyclization product 3 after dehydration.…”

“…As in the case of proline, the calculated distance of 2.5 Å in the SSanti-transition structure was favorable compared to the synenamine transition structure (3.5 Å). 22,23 Hanessian had initially observed flattening of the pyrrolidine ring of the ciscongener 4 in the crystalline solid state possibly resulting from potential steric repulsion of the carboxylic acid group with the cyclopropane ring. 24 This led Cheong and Houk to suggest a more planar enamine geometry that allows an easier transition to the anti-iminium transition structure (Fig.…”

Recyclable L-proline organocatalyst for Wieland–Miescher ketone synthesis

“…1b Hanessian et al documented that cis-(2S, 4S, 5S)-4, 5-methanoproline as an alternative catalyst of L-proline, offers the Wieland-Miescher ketone analogues with 93% enantiomeric excess along with good yield, whereas catalysis with trans-(2S, 4S, 5S)-4,5-methanoproline proceeded at much slower rate than L-proline and offers enone with lower selectivity (83% ee). 3 There are relatively few examples where primary amino acids were used as enantioselective catalyst for this reaction such as L-phenylalanine gave (S) enone 85% yield with 25% e.e., while L-tert-leucine offers (S)-ketone with higher yield (95%) but lesser enantiomeric excess (only 2%). 4a Various proline derivatives such as D-proline (6 days, 82% yield), L-proline (5 days, 56% yield) etc.…”