Lithium Enolates in the Enantioselective Construction of Tetrasubstituted Carbon Centers with Chiral Lithium Amides as Noncovalent Stereodirecting Auxiliaries

Abstract

Lithium enolates derived from carboxylic acids are ubiquitous intermediates in organic synthesis. Asymmetric transformations with these intermediates, a central goal of organic synthesis, are typically carried out with covalently attached chiral auxiliaries. An alternative approach is to utilize reagents that form discrete, well-defined aggregates with lithium enolates, providing a chiral environment conducive of asymmetric bond formation. These reagents effectively act as non-covalent, or traceless, chiral auxiliaries. Lithium amides are an obvious choice for such reagents as they are known to form mixed aggregates with lithium enolates. We demonstrate here that mixed aggregates can effect highly enantioselective transformations of lithium enolates in several types of reactions most notably in transformations forming tetrasubstituted and quaternary carbon centers. Easy recovery of the chiral reagent by aqueous extraction is another practical advantage of this one-step protocol. Crystallographic, spectroscopic, and computational studies of the central reactive aggregate, which provide insight into the origins of selectivity, are also reported.

Direct Asymmetric Alkylation of Ketones: Still Unconquered

“…[2] For example we now have methods for the direct α- alkylation of aldehydes [3] and carboxylic acids. [4] Thus it is perhaps surprising that the general, direct asymmetric alkylation (including allylation) of ketones remains elusive. Even the most simple asymmetric alkylation reactions involving ketones have not been reported (Figure 1b).…”

Catalytic Enantioselective Aldol Reactions of Unprotected Carboxylic Acids under Phosphine Oxide Catalysis

“…Whereas “masked” derivatives of carboxylic acids, such as esters and amides, have been frequently employed in stereoselective aldol reactions, asymmetric variants employing unprotected carboxylic acids have been rare . While the groups of Mulzer, Zakarian, and Fringuelli developed asymmetric aldol reactions of carboxylic acids, their procedures required stoichiometric amounts of chiral reagents to realize enantioselectivity (Scheme a, b). To the best of our knowledge, catalytic variants of asymmetric aldol reactions of carboxylic acids have not been reported to date.…”

“…Whereas "masked" derivatives of carboxylic acids,s uch as esters and amides,h ave been frequently employed in stereoselective aldol reactions,asymmetric variants employing unprotected carboxylic acids have been rare. [4][5][6][7][8][9] While the groups of Mulzer, [4] Zakarian, [5] and Fringuelli [6] developed asymmetric aldol reactions of carboxylic acids,t heir procedures required stoichiometric amounts of chiral reagents to realize enantioselectivity (Scheme 1a,b). To the best of our knowledge,catalytic variants of asymmetric aldol reactions of carboxylic acids have not been reported to date.Considering the high demand for carboxylic acids,their direct catalytic aldol reaction represents an ew tool in complex molecule synthesis.Recently,Kanai and co-workers developed an asymmetric Mannich-type reaction of carboxylic acids by using ac ombination of catalytic borane and ac hiral binol, [10] but the reaction was limited to imine electrophiles,a nd the use of carbonyl electrophiles as aldol acceptors has remained difficult.…”

Siloxy Esters as Traceless Activator of Carboxylic Acids: Boron-Catalyzed Chemoselective Asymmetric Aldol Reaction

“…Catalytic Chemoselective Activation of Carboxylic Acids promoting a catalytic asymmetric aldol reaction of carboxylic acids, 10 another fundamental and synthetically useful C-C bond-forming reaction. [11][12][13][14] Here we found that in-situ pre-conversion of carboxylic acids to siloxy esters dramatically facilitated the boron-catalyzed, carboxylic acid-selective asymmetric aldol reaction. The siloxy group worked as a traceless activator, allowing for the direct use of carboxyl group-containing multifunctional drugs and natural products themselves as substrates of catalytic asymmetric aldol reactions.…”