Stoichiometric Reactions of Enamines Derived from Diphenylprolinol Silyl Ethers with Nitro Olefins and Lessons for the Corresponding Organocatalytic Conversions – a Survey

Abstract

The stoichiometric reactions of enamines prepared from aldehydes and diphenyl-prolinol silyl ethers (intermediates of numerous organocatalytic processes) with nitro olefins have been investigated. As reported in the last century for simple achiral and chiral enamines, the products are cyclobutanes (4 with monosubstituted nitro-ethenes), dihydro-oxazine N-oxide derivatives (5 with disubstituted nitroethenes), and nitro enamines derived from g-nitro aldehydes (6, often formed after longer reaction times). The same types of products were shown to be formed, when the reactions were carried out with peptides H-Pro-Pro-Xaa-OMe that lack an acidic H-atom. Functionalized components such as alkoxy enamines, nitro-acrylates, acetamido-nitro-ethylene, or hydroxylated nitro olefins also form products carrying the diphenyl-prolinol silyl ether as a substituent. All of these products must be considered intermediates in the corresponding catalytic reactions; the investigation of their chemical properties provided useful hints about the rates, the conditions, the catalyst resting states or irreversible traps, and/ or the limitations of the corresponding organocatalytic processes. High-level DFT and MP2 computations of the structures of alkoxy enamines and thermodynamic data of a cyclobutane dissociation are also described. Some results obtained with the stoichiometrically prepared intermediates are not compatible with previous mechanistic proposals and assumptions.

One‐Pot Synthesis of (−)‐Oseltamivir and Mechanistic Insights into the Organocatalyzed Michael Reaction

“…Although the transition‐state model TS‐2 may also explain the diastereo‐ and enantioselectivities achieved, a more complicated sequence might exist during the reaction course. For example, we found that 14 exists as its cis isomer in CDCl 3 ( cis / trans =>99:1), whereas the trans isomer prevails in DMSO ( cis / trans =7:93) 11. The isomerization from cis to trans isomer might need to be considered.…”

“…The effect of acid additives : In our recent publication,11 we investigated the key Michael reaction of 2 with 3 or 14 , catalyzed by diphenylprolinol silyl ethers, in which the enamine generated from the α‐alkoxyaldehyde reacts with the nitroalkene to generate cyclobutane intermediates. The E / Z ratio of the enamine was found to be 1.0:1.6 and the E enamine preferentially reacts with ( E )‐ 3 , whereas the Z enamine reacts faster with ( Z )‐ 14 .…”

Role of Hydrogen‐Bonding Acceptors in Organo‐Enamine Catalysis

“…An acid may also activate the electrophile ( E + in Scheme ) in stage 2. It also has been reported that acid could catalyze the hydrolyses of ′′stable′′ intermediates (catalyst traps) to regenerate the chiral secondary amine catalyst 12. But the use of acid is not without problems.…”

Remote 1,6‐Stereocontrol by Iminium‐mediated Organocatalytic Events

“…On top of solvent phenomena, it is thus a real challenge to predict or explain the subtle configurational and conformational interplay between the electronic, orbital and steric states of a stereo‐defining event for a nucleophile‐catalyst‐electrophile triad within a complex milieu of organocatalytic equilibria, resting‐states, and additives 8. Nevertheless, a selection of enantioselective, 1,6‐conjugate additions3 are beginning to be discovered that proceed via remote, iminium‐mediated catalytic events (Scheme ) 9.…”