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 chiral reagents that form discrete, well-defined aggregates with lithium enolates, providing a chiral environment conducive of asymmetric bond formation. These reagents effectively act as noncovalent, 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 classes 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.

Figure 1 |. Strategies for forming quaternary stereocenters.

a, Auxiliary-directed stereoselective transformation of a lithium enolate. b, Chiral lithium amide-based (traceless) auxiliary.

Figure 2 |. Enantioselective construction of tetrasubstituted and quaternary carbon centers via lithium enediolate alkylation with chiral lithium amides as non-covalent stereodirecting auxiliaries.

The reactive aggregate was generated by incubating the carboxylic acid, the tetramine reagent (1:1 molar ratio), and 4.0 equiv of alkyllithium reagent in tetrahydrofuran (THF) at 0 °C for 2 h. Alkylations were carried out at –78 °C unless noted otherwise. Enantiomeric excess (ee) was determined with high-performance liquid chromatography; all have been corrected to bases with the R configuration as shown. a, Alkylation reagent was varied. b, Carboxylic acid was varied. *Isolated yield after methyl ester formation. ^†Alkylation was conducted at –40 °C. ^‡3-Bromocyclohexene was used as the reagent. ^§sec-butyllithium was used instead of n-butyllithium (n-BuLi).

Figure 3 |. Enantioselective construction of tetrasubstituted and quaternary carbon centers via lithium enediolate conjugate addition or aldol reaction with chiral lithium amides as non-covalent stereodirecting auxiliaries.

The reactive aggregate was generated by incubating the carboxylic acid, the tetramine reagent (1:1 molar ratio), and 4.0 equiv of alkyllithium reagent in tetrahydrofuran (THF) at 0 °C for 2 h. Reactions were carried out at –78 °C unless noted otherwise. Enantiomeric excess (ee) was determined with high-performance liquid chromatography; all results shown have been corrected to bases with the R configuration as shown. a, Unsaturated ester (Michael acceptor) was varied in the enantioselective conjugate addition. Synthesis of 4b was performed on a 4.1 g scale with a 98% recovery of the tetramine reagent (R)-¹TA via simple aqueous extraction. b, Carboxylic acid was varied in the enantioselective conjugate addition. c, Preliminary observations for the enantioselective aldol reaction with chiral lithium amides as non-covalent stereodirecting auxiliaries. *Isolated yield after methyl ester formation. i-Pr₂NLi (2.0 equiv) was used for enediolate formation. dr, diastereomeric ratio; n-BuLi, n-butyllithium.

Figure 4.

a) a drawing of the lithium amide-lithium enediolate aggregate from (R)-¹TA and 1a obtained by X-ray crystallographic analysis.

Figure 5.

Four conformational isomers of structure 6 determined by DFT computations with MP2 corrections. Conformer 6c corresponds to that seen crystallographically. Energies below the structures correspond to relative ground state energies. Energies on the arrows correspond to the relative energies of methylation by MeCl of each isomer via transition structures requiring no dissociation of a THF ligand from the geminally disolvated enolate lithium. The ∆∆G^‡ values are referenced to each respective isomer. The preferences for facial attack are obtained by referencing all to a single ground state (6c) and obtained by summing the relative conformer energies and the relative activation energies.