Asymmetric alkylation of 5-alkyl-2-aminothiazolones using a C2-symmetric chiral tetraamine base

Frizzle, Matthew J.; Nani, Roger R.; Martinelli, Michael J.; Moniz, George A.

doi:10.1016/j.tetlet.2011.08.073

Cited by 9 publications

(13 citation statements)

References 7 publications

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“…[2,3] Amgen [2] effected asymmetric alkylations of simple enolates en route to Correspondence to: David B. Collum; Armen Zakarian. Supporting information for this article is given via a link at the end of the document.…”

Section: Introductionmentioning

confidence: 99%

“…[5] The preference illustrated in Equation (2) has proven immutable in all mixed aggregates prepared from dianion 1. (2) Variable-temperature NMR spectroscopic studies revealed moderately temperaturedependent 6 Li chemical shifts and strikingly temperature-dependent 15 N chemical shifts ( Figure 3). The two anionic amido 15 N resonances changed markedly with temperature, whereas the chelating piperidino resonances were unaffected.…”

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confidence: 99%

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Mixed Aggregates of the Dilithiated Koga Tetraamine: NMR Spectroscopic and Computational Studies

Mack

Liang

et al. 2016

Angewandte Chemie

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A combination of 1 H, 6 Li, 13 C, and 15 N NMR spectroscopies and density functional theory computations explores the formation of mixed aggregates by a dilithium salt of a C 2 -symmetric chiral tetraamine (Koga's base). Lithium halides, acetylides, alkoxides, and monoalkylamides form isostructural trilithiated mixed aggregates with few exceptions. 6 Li-13 C and 6 Li-15 N couplings reveal heretofore undetected transannular contacts (laddering) with lithium acetylides and lithium monoalkylamides. Marked temperature-dependent 15 N chemical shifts seem to be affiliated with this laddering. Computational studies shed light on the general structures, penchant for laddering, and stereochemical consequences of aggregation. Graphical AbstractKoga's chiral dilithium amide used in asymmetric synthesis is shown to promiscuously form mixed aggregates with a wide variety of lithium salts including those containing halides, alkoxides, acetylides, and amides. Although largely isostructural, the presence or absence of Li-X transannular contacts distinguishes ladder from cyclic motifs. KeywordsLithium; NMR Spectroscopy; Aggregation; Synthetic Methods; Enantioselectivity C 2 -symmetric dilithiated tetraamine 1, developed by Koga and coworkers [1] as a chiral Brønsted base, has proven to be a versatile, non-covalent auxiliary for enantioselective synthesis. [2,3] Amgen [2] effected asymmetric alkylations of simple enolates en route to Correspondence to: David B. Collum; Armen Zakarian. Supporting information for this article is given via a link at the end of the document. (1)], and one of us (AZ) [3] developed enantioselective asymmetric alkylations and 1,4-additions of enediolates (Scheme 1). [4] The exceptional selectivities prompted a collaboration to study the structures of putative mixed aggregates derived from dilithiated enediolates and dianion 1. [5] Despite the potential complexities of characterizing mixtures of two dianions, mixed aggregates 2 (containing n-BuLi) and 3 (containing dilithium enediolate) proved structurally tractable and yielded a computationally viable and predictive stereochemical model. [5] (1) HHS Public AccessInstances in which highly stereoselective organolithium reactions have been traced to specific solvation and aggregation effects, [6] control of aggregate structure appears to accompany-and possibly be a prerequisite for-high stereocontrol. With that hypothesis in mind, we surveyed the structures of mixed aggregates of 1 with a variety of lithium salts (Chart 1). Dianion 1 is a promiscuous pairing partner, affording isostructural mixed aggregates 4 or the corresponding ladder structures 5 (distinguished by a transannular Li-X contact). [7] Spectroscopic and computational studies revealed structural nuances, including the stereochemical consequences of aggregation. [8][9][10] Mixed aggregation of 1 was examined with 6 Li NMR spectroscopy. We routinely used minor excesses of n-BuLi-derived mixed aggregate 2 to generate the new mixed aggregates from LiX precursors, which caused low conce...

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Section: Introductionmentioning

confidence: 99%

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Mixed Aggregates of the Dilithiated Koga Tetraamine: NMR Spectroscopic and Computational Studies

Mack

Liang

et al. 2016

Angewandte Chemie

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“…12 From the onset, the reactions were characterized by facile, highly anti-selective 1,4-additions with high conversions at −78 °C. 13 Piperidine-based tetramine ( R )- 1 TA , 14 which was previously shown to be highly effective in asymmetric alkylations of arylacetic acids, again proved to be optimal (88% yield, >30:1 dr, 83% ee; entry 1). One of the most striking observations is that a seemingly minor adjustment in the structure of the base, i.e., replacing the piperidine unit with pyrrolidine as in ( R )- 2 TA , resulted in reversal of the enantiomeric preference, giving the opposite enantiomer ent - 3 as the major product with 84% ee and 17:1 dr (entry 2).…”

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Direct Enantioselective Conjugate Addition of Carboxylic Acids with Chiral Lithium Amides as Traceless Auxiliaries

et al. 2015

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Michael addition is a premier synthetic method for carbon–carbon and carbon–heteroatom bond formation. Using chiral dilithium amides as traceless auxiliaries, we report the direct enantioselective Michael addition of carboxylic acids. A free carboxyl group in the product provides versatility for further functionalization, and the chiral reagent can be readily recovered by extraction with aqueous acid. The method has been applied in the enantioselective total synthesis of the purported structure of pulveraven B.

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“…The stereodirecting auxiliary group is formed in situ, temporarily bound to the reactive intermediate, and removed for recycling by simply quenching the reaction. 16,17,18,19,20,21 The well-documented and structurally defined aggregates comprising lithium enolates and lithium amides translate this general concept into practice. 22,23 The enantioselective construction of tetrasubstituted carbon centers sets a high bar for validating this approach.…”

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

Lü

Jackson

et al. 2016

J. Am. Chem. Soc.

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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.

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Asymmetric alkylation of 5-alkyl-2-aminothiazolones using a C2-symmetric chiral tetraamine base

Cited by 9 publications

References 7 publications

Mixed Aggregates of the Dilithiated Koga Tetraamine: NMR Spectroscopic and Computational Studies

Mixed Aggregates of the Dilithiated Koga Tetraamine: NMR Spectroscopic and Computational Studies

Direct Enantioselective Conjugate Addition of Carboxylic Acids with Chiral Lithium Amides as Traceless Auxiliaries

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

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