Chiral Lithium Research Articles

Mixed Aggregates of an Alkyl Lithium Reagent and a Chiral Lithium Amide Derived from N-Ethyl-O-triisopropylsilyl Valinol

The crystal structure of a mixed aggregate containing lithiated (S)-N-ethyl-3-methyl-1-(triisopropylsilyloxy)butan-2-amine derived from (S)-valinol and cyclopentyllithium is determined by X-ray diffraction. The mixed aggregate adopts a ladder structure in the solid state. The ladder-type mixed aggregate is also the major species in a toluene-d8 solution containing an approximately 1:1 molar ratio of the lithiated chiral amide to cyclopentyllithium. A variety of NMR experiments including diffusion-ordered NMR spectroscopy (DOSY) with diffusion coefficient-formula (D-FW) weight correlation analyses and other one- and two-dimensional NMR techniques allowed us to characterize the complex in solution. Solution state structures of the mixed aggregates of n-butyl, sec-butyllithium, isopropyllithium with lithiated (S)-N-ethyl-3-methyl-1-(triisopropylsilyloxy)butan-2-amine are also reported. Identical dimeric, ladder-type, mixed aggregates are the major species at a stoichiometric ratio of 1:1 lithium chiral amide to alkyllithium in toluene-d8 solution for all of the different alkyllithium reagents.

Chiral Bases as Useful Probes of Lithium Amide Reactivity

Experiments involving competition between chiral and achiral lithium amides provide a qualitative impression of the kinetics of different amide motifs in enolization reactions. The level of enantioselectivity was not diminished by the inclusion of lithium diisopropylamide (LDA; see scheme) into asymmetric enolizations mediated by a chiral lithium amide base, derived from a 1,2-diamine. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Approaches to the enantioselective synthesis of ferrugine and its analogues

A four-step synthetic route, to ferrugine (2α-benzoyltropane), its methyl analogue (2-acetyltropane) and their N-benzyl analogues is reported. The reaction sequence uses tropinone or N-benzylnortropinone aldols as key intermediates. Reduction of aldol derived N-tosylhydrazones and oxidation of the side chain hydroxyl group followed by spontaneous diastereomer equilibration provides the final products. Relative configuration of the exo,anti N-methyl and N-benzyl aldols was retained during N-tosylhydrazone formation. The relative stereochemistry of N-tosylhydrazones was assigned by single crystal diffraction. The final products, ferrugine and its methyl analogue, were synthesized in enantiomerically pure form via asymmetric deprotonation of tropinone using chiral lithium amide/lithium chloride aggregate prepared in situ from (S,S)-N,N-bis(1-phenylethyl)amine hydrochloride.

Structure of the Mixed Aggregates between a Chiral Lithium Amide and Phenyllithium or Vinyllithium

The structures, in THF, of 1:1 mixed aggregates of phenyllithium or vinyllithium with a chiral lithium amide derived from a 3-aminopyrrolidine are proposed on the basis of a multinuclear (1H, 6Li, 13C) NMR spectroscopic and DFT theoretical studies. In both cases, the lithium amide adopts an azanorbornyl-like folding and establishes stable coordinations with the C sp2 reactants, leading to rigid complexes that are expected to be at the origin of the inductions observed for the alcohols resulting from the condensation of these mixed aggregates on ortho-tolualdehyde.

A computational study of the enantioselective addition of n-BuLi to benzaldehyde in the presence of a chiral lithium N,P amide

In the presence of a chiral lithium N,P amide, alkylation of benzaldehyde results in an enantioselective formation of 1-phenyl-pentanol. This stereoselective addition reaction has herein been studied using dispersion-corrected density functional theory. For five different chiral ligands originating from amino acids the resulting enantioselectivity has been computationally determined and compared with experimentally available enantiomeric ratios (e.r.). In all cases the experimentally preferred enantiomer could be reproduced by the computational model. The selectivity trend among the ligands was found strongly sensitive to the amount of dispersion correction included. The origin of selectivity in the alkylation reaction is found to be composed of many combined interactions. For the most selective ligand 2A the most important factors found, which are favouring the (R)-TS, are a CH-π interaction between benzaldehyde-dimethyl ether (DME), stronger Li-solvation, and Li-π interactions with the phenyl ring in the backbone of the chiral lithium N,P amide. In addition, solvation by the bulk solvent and the size of the substituent on the nitrogen are also found important factors for the enantioselectivity.

ChemInform Abstract: Highly Enantioselective Direct Alkylation of Arylacetic Acids with Chiral Lithium Amides as Traceless Auxiliaries.

A direct, highly enantioselective alkylation of arylacetic acids via enediolates using a readily available chiral lithium amide as a stereodirecting reagent has been developed. This approach circumvents the traditional attachment and removal of chiral auxiliaries used currently for this type of transformation. The protocol is operationally simple, and the chiral reagent is readily recoverable.

ChemInform Abstract: Enantioselective Synthesis of Siloxyallenes from Alkynoylsilanes by Reduction and a Brook Rearrangement and Their Subsequent Trapping in a [4 + 2] Cycloaddition.

AbstractA consecutive process is developed for the enantioselective formation of siloxyallenes such as (II) from alkynoylsilanes (I), taking advantage of reduction by a chiral lithium amide followed by stereoselective SE′‐type process through the Brook rearrangement of an alkynyl silicate intermediate.

Stereoselectivity in (Z)‐Vinylmetal Additions to the Dictyostatin C1–C9 β‐Silyloxy Aldehyde

Abstract(Z)‐Vinyl iodides 6a–d were synthesized in high yield with good diastereo‐ and enantioselectivity using a Marshall–Tamaru, Pd‐catalyzed allenylzinc reaction as the key step. The addition of 6a–d to the dictyostatin C1–C9 β‐silyloxy aldehyde 5 was carried out through the vinyllithium and lithium vinylzincate routes. The lithium vinylzincate additions always proceeded in higher yields and gave fewer side products than the corresponding vinyllithium additions. The configuration of the newly created C9 stereocenter was assigned through Rychnovsky's acetonide 13C NMR method. The diastereoselectivity in this particular type of (Z)‐vinylmetal addition reaction appears to be controlled by a subtle balance between the intrinsic stereochemical preference of the β‐silyloxy aldehyde (1,3‐anti‐selective) and that of the chiral lithium (Z)‐vinylzincates. The latter becomes more influential with increasing stereochemical complexity, that is, passing from a stereodyad (6a,6b) to a stereotriad (6c,6d).

Synthesis of α-CF3-Substituted Carbonyl Compounds with Relative and Absolute Stereocontrol Using Electrophilic CF3-Transfer Reagents

Evans-type chiral lithium imide enolates undergo diastereoselective α-trifluoromethylation with a hypervalent iodine-CF(3) reagent with up to 91% combined isolated yield and 97:3 dr. The resulting isolated diastereopure products can be further transformed into valuable products without racemization.

Diastereo- and enantioselective aldol reaction of granatanone (pseudopelletierine)

Granatanone (granatan-3-one, 9-methyl-9-azabicyclo[3.3.1]nonan-3-one, pseudopelletierine or pseudopelletrierin) undergoes deprotonation with lithium amides giving a lithium enolate, which reacts with aldehydes diastereoselectively giving exclusively exo isomers and anti/ syn selectivity up to 98:2. Granatanone can be enantioselectively lithiated by chiral lithium amides and the resulting non-racemic enolate can be reacted with aldehydes giving aldols with enantiomeric excess up to 93% (99% ee after recrystallization). The absolute and relative configuration of the aldol products was determined by NMR spectroscopy and X-ray analysis. Granatanone; aldol reaction; asymmetric synthesis; enantioselective deprotonation; chiral lithium amide.

Highly Enantioselective Direct Alkylation of Arylacetic Acids with Chiral Lithium Amides as Traceless Auxiliaries

A direct, highly enantioselective alkylation of arylacetic acids via enediolates using a readily available chiral lithium amide as a stereodirecting reagent has been developed. This approach circumvents the traditional attachment and removal of chiral auxiliaries used currently for this type of transformation. The protocol is operationally simple, and the chiral reagent is readily recoverable.

Lithium Binaphtholate Catalyzed Direct Asymmetric Aldol-Tishchenko Reaction

The direct aldol-Tishchenko reaction of ketones with aldehydes catalyzed by a chiral lithium binaphtholate is described. Initially, a mixture of monobenzoyl 1,3-diols is formed. Subsequent hydrolysis generates the 1,3-diols as single diastereomers and in high yield and enantiomeric excess. The catalyst is inexpensive and can be easily prepared.

ChemInform Abstract: Direct Enantioselective Aldol—Tishchenko Reaction Catalyzed by Chiral Lithium Diphenylbinaphtholate.

AbstractChiral lithium catalyst is effective in the aldol—Tishchenko, aldol—aldol—Tishchenko and Evans—Tishchenko reactions to afford the products with high yields and enantioselectivities.

Enantioselective Synthesis of Siloxyallenes from Alkynoylsilanes by Reduction and a Brook Rearrangement and Their Subsequent Trapping in a [4+2] Cycloaddition

A consecutive process is developed for the enantioselective formation of siloxyallenes such as (II) from alkynoylsilanes (I), taking advantage of reduction by a chiral lithium amide followed by stereoselective SE′-type process through the Brook rearrangement of an alkynyl silicate intermediate.

Synthesis of NS9544 Acetate

NS9544 acetate is a monoamine reuptake inhibitor that is a candidate for the treatment of neuropathic pain. After all attempts at a classical resolution of intermediate E failed, an asymmetric synthesis was undertaken in which the chirality was introduced by asymmetric deprotonation of tropinone A using the chiral lithium amide base B.

Easy Routes towards Chiral Lithium Binaphthylamido Catalysts for the Asymmetric Hydroamination of Amino‐1,3‐dienes and Aminoalkenes

AbstractThe preparation of chiral lithium salts of N,N′‐disubstituted binaphthyldiamines and their use as catalysts for asymmetric hydroamination/cyclisation of amino‐1,3‐dienes and aminoalkenes are reported. Several straightforward methods involving the combination of ligand with solutions of methyl‐ or [(trimethylsilyl)methyl]lithium (LiCH2TMS) by ex situ or in situ preparation have been investigated. The use of LiCH2TMS in an in situ procedure was revealed as theeasiest for carrying out reactions with reliable results by fine‐tuning the quantity of base. Screening of a variety of ligands led to the selection of binaphthyldiamines modified by benzyl, pyridyl or naphthyl groups for the cyclisation of conjugated aminodienes in pyrrolidine or piperidine with the highest stereo‐ and enantioselectivities described to date (up to 61 and 72 % ee, respectively). Primary and secondaryaminoalkenes are efficiently cyclised at room temperature, but with poor enantioselectivities.

NMR studies of chiral lithium amides with phosphine chelating groups reveal strong Li-P-interactions in ethereal solvents

Chiral lithium amides with a chelating diphenylphosphine group have previously been found to mediate excellent enantioselectivity in the asymmetric addition of alkyllithiums to benzaldehyde. NMR studies reveal for the first time that chiral lithium amides can form chelating dimeric complexes with P-Li interactions in both diethyl ether and THF. The two lithium atoms in the dimer are found to be non-equivalent, one of them is coordinated to two phosphines, detected by Li,P-couplings, while the other lithium is only solvent bound. Slow ethereal ligand exchange on the NMR time scale below –50 °C has been detected by C NMR. Excess of n-butyllithium generates mixed dimeric complexes in both diethyl ether and THF.

Direct Enantioselective Aldol−Tishchenko Reaction Catalyzed by Chiral Lithium Diphenylbinaphtholate

Chiral lithium diphenylbinaphtholate is an effective catalyst for the enantioselective aldol-Tishchenko reaction, affording 1,3-diol derivatives with three contiguous chiral centers and high stereoselectivities. Successive aldol-aldol-Tishchenko reactions gave a triol derivative with five consecutive chiral centers. The present reaction was applicable to highly enantioselective Evans-Tishchenko reduction.

Four hydroxyls are better than two. The use of a chiral lithium salt of 3,3′-bis-methanol-2,2′-binaphthol as a multifunctional catalyst of enantioselective Michael addition reactions

The catalytic performance of the Li salt of ( S)- or ( R)-3,3′-bis[bis-(phenyl)hydroxymethyl]-2,2′-dihydroxy-dinaphthalene-1,1′ (BIMBOL) in asymmetric Michael additions of malonic acid derivatives and toluedine has been studied. Nitrostyrene and cyclohex-2-enone were chosen as Michael acceptors. Efficient asymmetric C–C and C–N bond formations with ee’s of up to 95% at room temperature were observed. A transition state model of the malonic ester addition to cyclohex-2-enone has been proposed based on the molecular structure of the acetone solvate of BIMBOL. The impact of the catalyst self-association on its performance is also discussed.

Lithium acetylides as alkynylating reagents for the enantioselective alkynylation of ketones catalyzed by lithium binaphtholate

Chiral lithium binaphtholate effectively catalyzed the enantioselective alkynylation of ketones using lithium acetylide as an alkynylating agent. This is the first example of the catalytic enantioselective addition of lithium acetylide to carbonyl compounds without the aid of other metal sources.