Enantioselective Deprotonation Reaction Research Articles

New Potentially Chelating Chiral Magnesium Amide Bases for Use in Enantioselective Deprotonation Reactions

A series of chiral secondary amines, incorporating a 5- or 6-membered heterocycle, were synthesised and used to prepare novel chiral magnesium bisamide reagents. These amide bases were subsequently applied within asymmetric deprotonation reactions to probe the potential for chelation-assisted selectivity enhancement. Good levels of selectivity could be achieved (up to 87:13 e.r. (R:S)) across a range of prochiral cyclohexanone substrates when employing a thiophene-derived magnesium bisamide complex.

ChemInform Abstract: The Diastereoselective and Enantioselective Substitution Reactions of an Isoindoline-Borane Complex.

The alkylation of N-methylisoindoline–borane complex, using nBuLi in THF is diastereoselective, the substitution occurring predominantly syn to the borane group. Use of the sBuLi–sparteine reagent mixture in Et2O changes the diastereoselectivity observed and enables the reaction to be conducted enantioselectively, giving the chiral isoindoline–borane complexes in up to 89% ee. The relative and absolute configurations of the chiral products were established by X-ray structure determinations and NMR studies. The new asymmetric process is shown to be an enantioselective deprotonation reaction, and the intermediate organolithium is shown to be epimerisable.

Application of the ONIOM method to enantioselective deprotonation in the presence of spartein

The hybrid ONIOM method has been tested for enantioselective deprotonation reaction of N-Boc-pyrrolidine and N-Boc-piperidine using isopropyl-lithium in the presence of sparteine. This study investigates different partitions and level of theories of ONIOM method, while the results are reported with regular DFT and ONIOM calculations. The system requires partitioning into layers that are not ideal for ONIOM, and we assess the effect of the various places where the border region can be placed.

Syntheses of Natural Products and Biologically Active Compounds by Means of Enantioselective Deprotonation Strategy

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Syntheses of Natural Products and Biologically Active Compounds by Means of Enantioselective Deprotonation Strategy.

Enantioselective deprotonation reactions of prochiral 4, 4-disubstituted cyclohexanone, 3-substituted cyclobutanones and 3, 5-dioxygenated cyclohexanones with a chiral lithium amide bases in the presence of silylating agents, were carried out to give the corresponding silyl enol ethers. The silyl enol ether obtained from 4-methyl-4-tolylcyclohexanone was converted to (+) -α-cuparenone. On the other hand, the silyl enol ethers derived from 3-substituted cyclobutanones were utilized in the synthesis of naturally occurring (-) -methylenolactocine and several kinds of lignan lactones, and also in the synthesis of medicinally important compound, (R) - (-) -rolipram. Moreover, the silyl enol ethers prepared from prochiral 3, 5-dioxygenated cyclohexanones were employed as the starting materials in the synthesis of biologically important compounds, such as HMG-CoA reductase inhibitor and antiobesity agent, tetrahydrolipstatin, with the opposite mode of asymmetric induction even by using the same chiral amide base. Finally, a synthetic procedure for enantiomerically enriched 5-hydroxycyclohex-2-enone was established by elimination of the alkoxide group in the chiral silyl enol ether, which was further transformed into an inositol phosphatase inhibitor.

Enantioselective deprotonation reactions using polymer-supported chiral magnesium amide bases.

Novel and readily accessible polymer-supported chiral magnesium amide reagents have been prepared and shown to be effective in the asymmetric deprotonation of a series of prochiral cyclohexanones, affording good to excellent levels of both conversion and enantiomeric ratio (up to 93:7); the Merrifield-based chiral amine species has been shown to be readily recyclable.

Enantioselective deprotonation reactions using a novel homochiral magnesium amide base

A novel homochiral magnesium bisamide base system has been prepared and reacted with a series of prochiral ketones in the presence of TMSCl to give efficient formation of the corresponding enol ethers in enantiomeric ratios of up to 95∶5.

Construction of an enantiomerically pure 6-substituted 3,5-syn-dihydroxyhexanoic acid system by an enantioselective deprotonation strategy: formal synthesis of an antiobesity agent, (-)-tetrahydrolipstatin.

Preparation of 6-substituted 4-hydroxytetrahydro-2H-pyran-2-one (12), a key intermediate for the synthesis of (-)-tetrahydrolipstatin, was achieved in an optically pure form by employing an enantioselective deprotonation reaction of the prochiral bicyclic derivative (5) as a key step.

The diastereoselective and enantioselective substitution reactions of an isoindoline–borane complex

The alkylation of N-methylisoindoline–borane complex, using nBuLi in THF is diastereoselective, the substitution occurring predominantly syn to the borane group. Use of the sBuLi–sparteine reagent mixture in Et2O changes the diastereoselectivity observed and enables the reaction to be conducted enantioselectively, giving the chiral isoindoline–borane complexes in up to 89% ee. The relative and absolute configurations of the chiral products were established by X-ray structure determinations and NMR studies. The new asymmetric process is shown to be an enantioselective deprotonation reaction, and the intermediate organolithium is shown to be epimerisable.

ChemInform Abstract: Stereoselective Reactions. Part 28. Effects of the Alkyl Group at the Amide Nitrogen of Chiral Bidentate Lithium Amides on Enantioselective Deprotonation Reaction.

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Stereoselective reactions. 28. Effects of the alkyl group at the amide nitrogen of chiral bidentate lithium amides on enantioselective deprotonation reaction

Enantioselective deprotonation of 4-substituted cyclohexanones ( 1a∼d ) by chiral bidentate lithium amides ( (R)- 2a∼j ) having an alkyl- or a fluoroalkyl substituent at the amide nitrogen was examined. (R)- 2i having a 2,2,2-trifluoroethyl group at the amide nitrogen was found to be an excellent chiral base for the present deprotonation reaction. Structures of (R)- 2i in solution and solid state are discussed.

New chiral ferrocenyl building blocks for asymmetric reactions

The new C 2-symmetrical ferrocenyl amines 2 and 3 are easily prepared starting from the ketones 4. Their utility is demonstrated for enantioselective deprotonation reactions and highly diastereoselective alkylations of the amides 7.

Stereoselective Reactions. XXVII. Solution Structures of a Chiral Tridentate Lithium Amide in Relation to Enantioselective Deprotonation of 4-tert-Butylcyclohexanone.

^6Li- and 15N-NMR spectroscopic studies on the solution structures of a chiral tridentate lithium amide have revealed that it exists as a chelated monomer in which the lithium is tri-coordinated, as a chelated dimer in which the lithium is tetra-coordinated, or as a mixture of these two species depending upon the solvent used. It is concluded that lower Lewis acidity of the tri- and tetra-coordinated lithium compared to the di-coordinated lithium makes tridentate lithium amides inferior to dibentate lithium amides as bases in enantioselective deprotonation reaction.

Asymmetric synthesis using chiral bases

Studies have been made to design chiral bidentate lithium amides and chiral tetradentate amines, and to explore the use of these chiral bases for enantioselective formation and reactions of lithium enolates. Chiral bidentate lithium amides having a chiral amide nitrogen made by virtue of chelation were successfully applied to the enantioselective deprotonation reaction of prochiral cyclic ketones, the kinetic resolution of racemic cyclohexanone derivatives by deprotonation, and the regioselective deprotonation of optically active 3-keto steroids. Structures of some of these chiral bidentate lithium amides in the solid state and in solution were elucidated by X-ray and NMR spectroscopic analyses. By the use of chiral tetradentate amines, enantioselective reactions of lithium enolates with electrophiles, such as alkylation, protonation, and Michael addition, proceeded successfully. Examples of catalytic enantioselective deprotonation, alkylation, and protonation by the present strategy are also presented and discussed.

Crystallographic and lithium-6 and nitrogen-15 NMR studies of a chiral bidentate lithium amide. An effect of aggregation states on an enantioselective deprotonation reaction

Crystallographic and lithium-6 and nitrogen-15 NMR studies of a chiral bidentate lithium amide. An effect of aggregation states on an enantioselective deprotonation reaction