Chiral Lithium Research Articles

Enantioselective desymmetrisation of an epoxytropinone for peduncularine synthesis

A key 7-allyl-8-hydroxy-6-azabicyclo[3.2.1]octan-3-one intermediate in a synthesis of the alkaloid peduncularine is obtained enantioenriched, by desymmetrisation of an achiral 6,7-epoxy-8-azabicyclo[3.2.1]octan-3-one (epoxytropinone). Chiral lithium amide-assisted enantioselective silyl enol ether formation then TMSOTf/allyltrimethylsilane/2,6-lutidine-induced rearrangement−allylation proceeded in up to 80:20 er, but modest overall yield. Chiral amines or (thio)ureas replacing 2,6-lutidine gave up to 76:24 er directly from epoxytropinone. A direct, simplified (base-free) process using a BINOL-derived bis(sulfuryl)imide catalyst and allyltrimethylsilane proved the most promising (80%, 83:17 er).

Light-Mediated Chiral Phosphate Catalysis for Asymmetric Dicarbofunctionalization of Enamides

A light-mediated asymmetric dicarbofunctionalization of enamides with carboxylic-acid-derived redox-active esters (RAEs) and indoles has been established by using chiral lithium phosphate catalysis in the presence or absence of photoredox catalyst. This reaction features mild reaction conditions and broad substrate scopes, delivering a wide range of highly functionalized chiral amine derivatives. Mechanistic studies suggest that chiral lithium phosphate can serve as a pocket to accelerate the aggregation of enamide and RAE through hydrogen-bonding and coordination interaction, enabling the formation of a charge-transfer complex (CTC). Either enamide or CTC can be excited by direct irradiation or Ru(II)-mediated photosensitization to furnish chiral iminium intermediates for the asymmetric Friedel–Crafts reaction of indole.

Enantioselective Alkylation of 2-Alkylpyridines Controlled by Organolithium Aggregation.

Direct enantioselective α-alkylation of 2-alkylpyridines provides access to chiral pyridines via an operationally simple protocol that obviates the need for prefunctionalization or preactivation of the substrate. The alkylation is accomplished using chiral lithium amides as noncovalent stereodirecting auxiliaries. Crystallographic and solution NMR studies provide insight into the structure of well-defined chiral aggregates in which a lithium amide reagent directs asymmetric alkylation.

α-Alkylation of β,γ-Unsaturated Carboxylic Acids with Chiral Lithium Amides

α-Alkylation of β,γ-Unsaturated Carboxylic Acids with Chiral Lithium Amides

Direct Enantioselective and Regioselective Alkylation of β,γ-Unsaturated Carboxylic Acids with Chiral Lithium Amides as Traceless Auxiliaries.

Efficient asymmetric alkylation of β,γ-unsaturated carboxylic acids without prior functionalization is enabled by chiral lithium amides. Enantioselectivity is imparted by a putative mixed lithium amide-enediolate aggregate that acts a traceless auxiliary formed in situ, allowing for a direct asymmetric alkylation and a simple recovery of the chiral reagent.

Enantioselective deprotometalation of N,N-dialkyl ferrocenecarboxamides using metal amides

Our attempts to deprotometalate N,N-dialkyl ferrocenecarboxamides enantioselectively by using chiral lithium or lithium–zinc dialkylamides are reported.

Total synthesis of spiromastilactone A.

The total synthesis of spiromastilactone A is reported for the first time. A swift strategy is presented that involves a pivotal enantioselective nucleophilic 1,2-alkylation of an aldehyde prepared in four quantitative synthetic steps from commercial 2,4-dihydroxybenzoic acid. This key reaction, which was described very recently by our group and carried out here on a gram scale, involves cheap and easily accessible tricoordinated chiral lithium amido zincates. The resulting enantioenriched secondary alcohol is involved afterward in an efficient intramolecular cyclization providing the phthalide core of the target, and two quantitative additional steps aiming to deprotect the phenol groups then introduce chlorine atoms end the synthetic scheme. Spiromastilactone A is obtained in 44% overall yield in eight synthetic steps, among which six are quantitative, and the 89 : 11 enantiomeric ratio (78% ee value) is in favor of the right enantiomer (R configuration).

Corrigendum: Chiral Lithium Amido Zincates for Enantioselective 1,2-Additions: Auto-assembling Reagents Involving a Fully Recyclable Ligand.

The authors wish to state that Mathieu Rouen and Pauline Chaumont contributed equally to the work contained in this Communication. They should be considered as co-first authors. In addition, reference 11c contained incorrect page numbers. The corrected reference appears below. [11] c) A. Harrison-Marchand, G. Barozzino-Consiglio, J. Maddaluno, Chem. Rec. 2017, 17, 622–639.

Chiral Lithium Amido Zincates for Enantioselective 1,2-Additions: Auto-assembling Reagents Involving a Fully Recyclable Ligand.

A methodology consisting in carrying out enantioselective nucleophilic 1,2-additions (ee values up to 97 %) from cheap, easily accessible, and never described before, chiral lithium amido zincates is presented. These multicomponent reactants auto-assemble when mixing, in a 1:1 ratio, a homoleptic diorganozinc (R2 Zn) with a chiral lithium amide (CLA). The latter, obtained after a single reductive amination, plays the role of the chiral inductor and is fully recoverable thanks to a simple acid-base wash, allowing being recycled and re-use without loss of stereochemical information.

Enantioselective Conjugate Hydrocyanation of α,β-Unsaturated N-Acylpyrroles Catalyzed by Chiral Lithium(I) Phosphoryl Phenoxide

Enantioselective conjugate hydrocyanation of α,β-unsaturated N-acylpyrroles with the combined use of Me3SiCN, LiCN, and HCN has been developed in the presence of a chiral lithium(I) phosphoryl phenoxide catalyst. This reaction is useful for a variety of N-acylpyrroles, including previously unreported substrates, such as heteroaryl and halogen-substituted N-cinnamoylpyrroles. A gram-scale reaction and subsequent transformations to a (R)-succinate, (S)-paraconic acid, and (R)-baclofen demonstrate an entry for the practical synthesis of optically active β-substituted γ-aminobutyric acids (GABA).

Chiral lithium binaphtholate for enantioselective amination of acyclic α-alkyl-β-keto esters: Application to the total synthesis of l-carbidopa

A chiral lithium binaphtholate catalyzes the enantioselective amination of α-alkyl-β-keto esters with azodicarboxylates to produce optically active α,α-disubstituted α-amino acid derivatives in high yields and with good to high enantioselectivities. A stoichiometric amount of lithium hydroxide efficaciously improved both the reactivity and enantioselectivity of amination. The resulting aminated product is readily convertible to l-carbidopa.

Novel and practical asymmetric synthesis of β2,3-amino esters using asymmetric Michael addition of chiral amine

A practical method for the synthesis of chiral β2,3-amino esters having various substituents was developed, which is characterized by an asymmetric Michael addition reaction of a chiral lithium amide with trisubstituted (E)-α,β-unsaturated esters. We found that a highly face-selective protonation occurred by the quick addition of water to the enolate intermediate derived from the Michael addition reaction to afford N-protected β2,3-amino esters in moderate to excellent yields. This finding was made possible by the facile preparation of geometrically pure trisubstituted (E)-α,β-unsaturated esters, which was established recently by our group. The subsequent deprotection of the amino group in the Michael adduct by using N-iodosuccinimide (NIS) efficiently provided β2,3-amino esters having various substituents.

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

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.

Chiral Lithium Amides: Tuning Asymmetric Synthesis on the Basis of Structural Parameters.

An overview on the structural arrangements adopted by Chiral Lithium Amides (CLAs), alone or in mixed complexes, is presented. These species are important reagents for asymmetric synthesis and understanding their organization is essential to improve their design and the reaction conditions.

ChemInform Abstract: Reagent‐Controlled Lithiation‐Borylation

AbstractReview: 57 refs.

ChemInform Abstract: Enantioselective Amination of Acyclic α‐Alkylated β‐Keto Esters Catalyzed by Chiral Lithium Binaphtholate.

AbstractThe synthesis of optically active α,α‐disubstituted amino acid derivatives is achieved through asymmetric amination of β‐keto esters with azidodicarboxylates using a chiral lithium binaphtholate derived from BBI as catalyst.

Enantioselective amination of acyclic α-alkylated β-keto esters catalyzed by chiral lithium binaphtholate

The enantioselective amination of α-alkylated β-keto esters with azodicarboxylates using a chiral dilithium binaphtholate as catalyst affords optically active α,α-disubstituted α-amino acid derivatives in high enantioselectivities of up to 95% ee. A stoichiometric amount of lithium hydroxide accelerates the amination. This method provides easy access to various chiral α,α-disubstituted α-amino acids in high yields and with high enantioselectivities from readily available starting materials and chiral sources.

ChemInform Abstract: Enantioselective Synthesis of Silacyclopentanes.

AbstractFunctionalized silacyclopentanes are synthesized by enantioselective β‐elimination of silacyclopentene oxides and subsequent stereospecific transformations using a newly developed chiral lithium amide.

ChemInform Abstract: Enantioselective Cyanosilylation of Ketones with Lithium(I) Dicyanotrimethylsilicate(IV) Catalyzed by a Chiral Lithium(I) Phosphoryl Phenoxide.

A highly enantioselective cyanosilylation of ketones was developed by using a chiral lithium(I) phosphoryl phenoxide aqua complex as an acid/base cooperative catalyst. The pentacoordinate silicate generated in situ from Me3SiCN/LiCN acts as an extremely reactive cyano reagent. Described is a 30 gram scale reaction and the synthesis of the key precursor to (+)-13-hydroxyisocyclocelabenzine.

Enantioselective Cyanosilylation of Ketones with Lithium(I) Dicyanotrimethylsilicate(IV) Catalyzed by a Chiral Lithium(I) Phosphoryl Phenoxide

AbstractA highly enantioselective cyanosilylation of ketones was developed by using a chiral lithium(I) phosphoryl phenoxide aqua complex as an acid/base cooperative catalyst. The pentacoordinate silicate generated in situ from Me3SiCN/LiCN acts as an extremely reactive cyano reagent. Described is a 30 gram scale reaction and the synthesis of the key precursor to (+)‐13‐hydroxyisocyclocelabenzine.