Activated carboxylates, catalytic generation

The proposed catalytic cycle for this reaction begins with the initial attack of the in situ generated thiazolylidene carbene on the epoxyaldehyde followed by intramolecular proton transfer (Scheme 28, XXXII-XXXIII). Isomerization occurs to open the epoxide forming XXXIV which undergoes a second proton transfer forming XXXV. Diastereoselective protonation provides activated carboxylate intermediate XXXVI. Nucleophilic attack of the activated carboxylate regenerates the catalyst and provides the desired P-hydroxy ester. 

Recently, Bode et al. were able to demonstrate that the products formed after generation of the homoenolate equivalents 67 are determined by the catalytic base [64]. Strong bases such as KOt-Bu led to carbon-carbon bond-formation (y-butyrolactones), while weaker bases such as diisopropylethylamine (DIPEA) allowed for protonation of the homoenolate and the subsequent generation of activated carboxylates. The combination of triazolium catalyst 72 and DIPEA in THF as solvent required no additional additives and enabled milder reaction conditions (60 °C), accompanied by still high conversions in the formation of saturated esters out of unsaturated aldehydes (Scheme 9.21). Aliphatic and aromatic enals 62, as well as primary alcohols, secondary alcohols and phenols, are suitable substrates. a-Substituted unsaturated aldehydes did not yield the desired products 73. 

The broad scope of the catalytic generation of activated carboxylates was demonstrated by Bode et al. in the diastereoselective synthesis of / -hydroxy esters 79 from a,/ -epoxy aldehydes 80 employing achiral thiazolium salts 81 as precatalysts (Scheme 9.24) [67]. The incorporation of a reducible functionality into the aldehyde substrate is the premise for a catalyst-induced intramolecular redox reaction generating the activated carboxylate 82. 

Chow KYK, Bode JW (2004) Catalytic generation of activated carboxylates direct, stereoselective synthesis of fi-hydroxyesters from. J Am Chem Soc 126 8126-8127... 

Sohn SS, Bode JW (2005) Catalytic generation of activated carboxylates from enals a product-determining role for the base. Org Lett 7 3873-3876... 

The Bode group have documented an NHC-catalyzed enantioselective synthesis of ester enolate equivalents with a,p-unsaturated aldehydes as starting materials and their application in inverse electron demand Diels-Alder reactions with enones. Remarkably, the use of weak amine bases was crucial DMAP (conjugate acid = 9.2) andN-methyl morpholine (NMM, conjugate acid pAa = 7.4) gave the best results. A change in the co-catalytic amine base employed in these reactions could completely shift the reaction pathway to the hetero-Diels-Alder reaction, which proceeded via a catalytically generated enolate. An alternative pathway that occurred via a formal homoenolate equivalent was therefore excluded. It is demonstrated that electron-rich imidazolium-derived catalysts favor the homoenolate pathways, whereas tri-azolium-derived structures enhance protonation and lead to the enolate and activated carboxylates (Scheme 7.71). 

Since these initial reports, the NHC-catalyzed generation of activated carboxylates from a-functionalized aldehydes has been extended to a remarkably wide range of substrate classes. Bode first reported the generation of activated carboxylates from a,p-unsaturated aldehydes as part of his work on the catalytic generation of homoenolates vide infra) These studies were further explored to develop improved catalysts and render this a general process. This work, which identified the uniquely high reactivity of A-mesityl substituted triazolium pre-catalysts as superior to all other catalyst classes for NHC-catalyzed redox reactions of a,p-unsaturated aldehydes, was crucial to the development of the remarkable annulation reactions described below. Zeitler reported analogous... 

Scheme 14.5 Catalytic generation of activated carboxylates (DIPEA = A, Af-diisopropylethylamine).

Consideration of the reaction pathways shown in Scheme 14.12 for the NHC-catalyzed generation of activated carboxylates from enals reveals the intermediacy of an NHC-bound ester enol or enolate equivalent that could be trapped by a suitable electrophile. This was first achieved by Bode, who in 2006 reported highly enantioseleetive inverse electron-demand Diels-Alder reactions of the catalytically generated enolate equivalents and ot,p-unsaturated N-sul-fonyl imines (Scheme 14.19). At the time, this was the first report of a highly... 

The power of NHC catalysts lies in the ability of these heterocycles to promote the transient generation of reactive species, such as acyl anion equivalents or activated carboxylates. Using the mechanistic postulates for these processes, it is possible to predict that the combination of an NHC catalyst and an a,p-unsatu rated aldehyde could lead to the generation of a wide variety of catalytically generated reactive intermediates (Scheme 14.12). The rapid developments of new catalysts and reaction conditions have made possible the selective generation of each of these classes of reactive species, including the synthetically powerful homoenolate and ester enolate equivalents. 

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