Organocatalytic Preparation of Substituted Cyclopentanes: A Mechanistic Study

Abstract

The reaction mechanism of a tandem conjugate addition/α-alkylation of enals leading to functionalized cyclopentanes catalyzed by O-trimethylsilyldiphenylprolinol was investigated by mass spectrometry, NMR spectroscopy, and DFT calculations. We have shown that the high stereoselectivity of the reaction depends on the energy discrimination between the two stereoisomers formed by the condensation of the α,β-unsaturated aldehyde (cinnamaldehyde) and the catalyst. The stereoselectivity of this step depends on the solvent used. The experimental activation barriers were determined to be E(a) = 25 ± 7 kJ mol(-1) (Arrhenius equation), ΔH(‡) = 23 ± 7 kJ mol(-1), and ΔG(‡) = 101 ± 9 kJ mol(-1) (Eyring equation).

Recent Progress in Organocatalytic Asymmetric Domino Transformations

“…[115] It was proposedt hat the high stereoselectivity of this reaction was aresult of the energy discrimination between the two intermediatee namine stereoisomers (R)-271 and (S)-271,w here the latter was found to be more stable than the former. [115] Thes tereoselectivity also depended on the solvent used. An additional theoretical studyt oe valuate the reactionm echanism and the stereoselectivities in the diarylprolinols ilyl ether-catalyzed domino reactions hasb eenp erformed by Chen and co-workers.…”

Elusive Reaction Intermediates in Solution Explored by ESI‐MS: Reverse Periscope for Mechanistic Investigations

“…[39] Theemployment of achiral secondary amine as an organocatalyst is also advantageous for ESI-MS monitoring of the reaction mixture.Iminium adducts,infact, formed by condensation of the amine with the reactants first and finally with the product, can be sampled efficiently by ESI-MS,t hus allowing the characterization of the various reaction intermediates.Most interestingly tandem MS experiments opened awindow to the crucial cyclization event. Only av ery small amount of the protonated intermediate,w hich undergoes ring closure,forms before the intramolecular step and can thus be isolated in the gas phase and activated by CID for its characterization.…”

“…Back to the identification of reaction intermediates,i n addition to the Hantzsch and Morita-Baylis-Hillman reaction several research groups over the last few years have extensively explored the domain of organic transformations proceeding via iminum or enamine intermediates.R oithovµ and co-workers focused on the organocatalytic cascade reaction between an a,b-unsaturated aldehyde and amalonate derivative,f or the enantioselective preparation of cyclopentane rings. [39] Theemployment of achiral secondary amine as an organocatalyst is also advantageous for ESI-MS monitoring of the reaction mixture.Iminium adducts,infact, formed by condensation of the amine with the reactants first and finally with the product, can be sampled efficiently by ESI-MS,t hus allowing the characterization of the various reaction intermediates.Most interestingly tandem MS experiments opened awindow to the crucial cyclization event. Only av ery small amount of the protonated intermediate,w hich undergoes ring closure,forms before the intramolecular step and can thus be isolated in the gas phase and activated by CID for its characterization.…”

“…This evidence corroborates the hypothesis that the cyclization event is ap rerogative of suitable neutral enamine intermediates. [39] In as tudy on the synthesis of pyrazolones from Morita-Baylis-Hillman adducts by Coelho and co-workers, [40] hydrazinium ion intermediates were intercepted by ESI-MS,a nd the overall reaction mechanism of pyrazolone formation was investigated by employing ESI-MS/MS.…”

Elektrospray‐Massenspektrometrie: ein umgekehrtes Periskop zur Erforschung von Reaktionsmechanismen in Lösung

“…Nicht nur die Hantzsch‐ und MBH‐Reaktion, sondern auch viele andere organische Umsetzungen, die über Iminiumion‐ oder Enamin‐Zwischenstufen ablaufen, wurden von verschiedenen Forschungsgruppen in den letzten Jahren ausführlich untersucht. Roithová und Mitarbeiter konzentrierten sich auf die organokatalytische Reaktionskaskade zwischem einem α,β‐ungesättigten Aldehyd und einem Malonsäurederivat zur enantioselektiven Synthese von Cyclopentanringen . Ein chirales sekundäres Amin kann als Organokatalysator eingesetzt werden, um die Reaktionsmischung mithilfe von ESI‐MS überwachen zu können.…”