Chiral Nucleophiles Research Articles

The synthesis of an enantiopure planar-chiral Lewis acid complex via kinetic resolution and its application in stereoselective additions to imines

This report describes the synthesis and an application of a new planar-chiral Lewis acid based on a 1,2-azaborolyl framework. The enantiopure complex is generated through an intriguing kinetic resolution by a chiral nucleophile. Imines bind in excellent yield to the planar-chiral 1,2-azaborolyl, furnishing crystallographically characterizable adducts that adopt the conformation that had been anticipated on the basis of steric considerations. Nucleophiles add with high stereoselectivity to these complexes, with the predicted sense of asymmetric induction.

Net directed 180° aryl–aryl bond rotation in a prototypical achiral biaryl lactone synthetic molecular motor

Net directed 180° bond rotation was achieved through diastereoselective ring-opening reactions in an achiral biaryl lactone using a chiral nucleophile followed by re-lactonization. The efficiency of the directed bond rotation has been determined by HPLC–MS to be 50% and 20% with two different chiral nucleophiles. These results demonstrate the potential for a prototype of a chemically driven synthetic molecular motor which has the advantages of both simplicity and flexibility in operation and is the first example of the use of a chiral auxiliary to induce transient axial chirality resulting in net directed bond rotation.

Efficiency in Nonenzymatic Kinetic Resolution

AbstractFor Abstract see ChemInform Abstract in Full Text.

Efficiency in Nonenzymatic Kinetic Resolution

The Walden memorial at the Technical University in Riga is pictured in the frontispiece to mark the recent centennial of the Walden inversion. This is a rare public monument to key events from the first era of exploration in stereocontrolled synthesis, and may be the only such monument to use the language of organic chemistry expressed at the molecular level. The reaction of racemic substrates with chiral nucleophiles is one of many methods currently known to achieve kinetic resolution, a phenomenon that ranks as the oldest and most general approach for the synthesis of highly enantioenriched substances. The first nonenzymatic kinetic resolutions as well as the original forms of the Walden inversion were studied in the 1890s. All of these investigations were conducted within the first generation following the demonstration that carbon is tetrahedral, and provided abundant evidence that the principles and importance of enantiocontrolled syntheses were understood. However, a reliable, rapid technique to quantify results and guide the optimization process was still lacking. Many decades passed before this problem was solved by the advent of HPLC and GLPC assays on chiral supports, which stimulated explosive growth in the synthesis of nonracemic substances by kinetic resolution. The Walden monument is accessible to passers-by for hands-on inspection as well as for contemplation and learning. In a similar way, kinetic resolution is experimentally accessible and can be thought-provoking at several levels. We follow the story of kinetic resolution from the early discoveries through fascinating historical milestones and conceptual developments, and close with a focus on modern techniques that maximize efficiency.

Bifunctional Lewis Acid-Nucleophile-Based Asymmetric Catalysis: Mechanistic Evidence for Imine Activation Working in Tandem with Chiral Enolate Formation in the Synthesis of β-Lactams

We report a mechanistically based study of bifunctional catalyst systems in which chiral nucleophiles work in conjunction with Lewis acids to produce beta-lactams in high chemical yield, diastereoselectivity, and enantioselectivity. Chiral cinchona alkaloid derivatives work best when paired with Lewis acids based on Al(III), Zn(II), Sc(III), and, most notably, In(III). Homogeneous bifunctional catalysts, in which the catalyst contains both Lewis acidic and Lewis basic sites, were also studied in detail. Mechanistic evidence allows us to conclude that the chiral nucleophiles form zwitterionic enolates that react with metal-coordinated imines. Alternative scenarios, which postulated metal-bound enolates, were disfavored on the basis of our observations.

The Development of the Asymmetric Morita—Baylis—Hillman Reaction Catalyzed by Chiral Brønsted Acids

AbstractThis report describes the development of a chiral Brønsted acid‐catalyzed asymmetric Morita–BaylisHillman (MBH) reaction of cyclohexenone with aldehydes. During the course of our studies on chiral Lewis acid‐promoted MBH reactions, we discovered that chiral binaphthol‐derived Brønsted acids serve as promoters of the asymmetric MBH reaction. We propose that the phosphonium enolate of cyclohexenone is stabilized via hydrogen‐bonding with the binaphthol‐derived Brønsted acid, creating a chiral nucleophile. A practical and efficient set of conditions was developed using stoichiometric PEt3 as the nucleophilic promoter and catalytic amounts of a binaphthol‐derived Brønsted acid to effect the reaction of cyclohexenone with various aliphatic and aromatic aldehydes in good yields and enantiomeric excesses (up to 96% ee).

Molecular mechanics calculations as predictors of enantioselectivity for chiral nucleophile catalyzed reactions

We present molecular mechanics (MM) calculations as models of activated complexes for the β-lactam forming [2+2] cycloaddition between imino ester 4 and the zwitterionic intermediates derived from ketenes and various chiral nucleophilic catalysts. Our method employs the use of Monte Carlo conformational searches utilizing the MMFF force field contained within the Macromodel program. These models accurately predict the sense of stereochemical induction observed experimentally. Also, the predicted energetic differences for minima leading to (R) or (S)-derived ketene facial selectivity correlate in a general sense with the magnitude of the enantioselectivity. This work establishes that our approach represents a viable method for the design of new nucleophilic catalysts a priori using MM calculations.

Bifunctional Asymmetric Catalysis: A Tandem Nucleophile/Lewis Acid Promoted Synthesis of β‐Lactams.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Bifunctional asymmetric catalysis: a tandem nucleophile/Lewis acid promoted synthesis of beta-lactams.

[reaction: see text]. We describe a superior procedure for the catalytic, asymmetric synthesis of beta-lactams using a bifunctional catalyst system consisting of a chiral nucleophile and an achiral Lewis acid.

ChemInform Abstract: The Asymmetric Addition of Trimethylsilylcyanide to Aldehydes Catalyzed by Anionic Chiral Nucleophiles. Part 1.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: The Asymmetric Addition of Trimethylsilylcyanide to Aldehydes Catalyzed by Anionic Chiral Nucleophiles. Part 2.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Stereoselective synthesis of 3-alkylsulfinylmethylisoxazolines and their use as chiral nucleophiles in the chain elongation of 2,3- O-isopropylidene- d-glyceraldehyde

The reaction of racemic 3-methylisoxazolines and enantiomerically pure ( R S)- and ( S S)-methanesulfinates and ( R S)- and ( S S)-ethanesulfinates of 1,2:5,6-di- O-isopropylidene- d-glucofuranose allows enantiomerically pure 3-alkylsulfinylmethylisoxazolines with both absolute configurations at sulfur to be obtained. One of these has been used as a chiral nucleophile in the four carbon homologation of 2,3- O-isopropylidene- d-glyceraldehyde 17.

The asymmetric addition of trimethylsilylcyanide to aldehydes catalysed by anionic chiral nucleophiles. Part 2

Studies have been carried out on the addition of trimethylsilylcyanide to aldehydes using highly active chiral lithium phenolate catalysts. The screening of a number of chiral phenolates has resulted in a system which gives the TMS ethers of cyanohydrins in excellent chemical yields with enantiomeric excesses of up to 97%.

The asymmetric addition of trimethylsilylcyanide to aldehydes catalysed by anionic chiral nucleophiles. Part 1

Trimethylsilylcyanide has been added to a number of aldehydes using a highly active chiral catalyst. This procedure gives the TMS ethers of the corresponding cyanohydrins in excellent chemical yields with enantiomeric excesses of up to 59%. The reaction is believed to occur through hypervalent silicon intermediates.

Catalytic enantioselective addition to imines.

Chiral nitrogen-containing compounds are widely distributed in nature and include many biologically important molecules (Chart 1). In these compounds, the nitrogen-containing units are known to play important roles for their bioactivities. For the synthesis of these chiral nitrogen-containing building blocks, use of imines as electrophiles is the most promising and convenient route.1 While many approaches using chiral imines or chiral nucleophiles have been reported,1 these diastereoselective reactions have some disadvantages. First, the procedures to introduce chiral auxiliaries to substrates and to remove them after the diastereoselective reactions are often tedious. Second, more than stoichiometric amounts of chiral sources are needed to obtain chiral compounds according to these reactions. On the other hand, catalytic enantioselective reactions provide the most efficient methods for the synthesis of chiral compounds,2 because large quantities of chiral compounds are expected to be prepared using small amounts of chiral sources. While much progress has been made recently in catalytic enantioselective reactions of aldehydes and ketones such as aldol,3 allylation,4 Diels-Alder,5 cyanation reactions,6 reduction,1b,2b etc., progress in catalytic enantioselective reactions of imines is rather slow. There are some difficulties in performing catalytic enantioselective reactions of imines. For example, in the cases of chiral Lewis acid promoted asymmetric Shū Kobayashi was born in 1959 in Tokyo, Japan. He studied chemistry at the University of Tokyo and received his Ph.D. in 1988 (Professor T. Mukaiyama). After spending 11 years at Science University of Tokyo (SUT), he moved to Graduate School of Pharmaceutical Sciences, University of Tokyo, in 1998. His research interests include development of new synthetic methods, development of novel catalysts (especially chiral catalysts), organic synthesis in water, solid-phase organic synthesis, total synthesis of biologically interesting compounds, and organometallic chemistry. He received the first Springer Award in Organometallic Chemistry in 1997.

The Atropisomer-Selective Ring Cleavage of Helically Distorted, Configuratively Unstable Biaryl Lactones with a Chiral Metallated N -Nucleophile - the Complete PM3 Mechanistic Course and its Video Presentation

The complete mechanistic sequence of the atropo-diastereoselective ring opening reaction of configuratively unstable lactone-bridged biaryls with the chiral 2R,5R-1-lithio-2,5-dimethylpyrrolidine was calculated using the semiempirical PM3 method. It was shown that the stereochemically deciding key step of the reaction sequence is the first attack of the chiral nucleophile to the carbon atom of the lactone moiety. The diastereoselectivity of this synthetically useful and mechanistically challenging biaryl synthesis was found to originate from a dynamic kinetic resolution of the axially chiral, but configuratively unstable lactone substrates. For a further understanding of the complex stereochemical process, the geometries resulting from IRC-calculations have been visualized and are presented as an Quicktime-movie.

Asymmetric Catalytic Reduction of Ketones with Hypervalent Trialkoxysilanes

The catalytic asymmetric reduction of different ketones1 with transient hypervalent silicon hydrides is described. Trialkoxysilanes, upon activation by a small amount of a chiral nucleophile, underwent addition to the carbonyl group, forming the corresponding silyl protected alcohols, which were cleaved during the workup to give the enantiomerically enriched product alcohols. A brief screening of the reaction parameters and the results are summarized below.

Principles of asymmetric synthesis

Introduction. Why we do asymmetric synthesis. What is an asymmetric synthesis? Stereoselectivity: intraligand vs. interligand asymmetric induction. Selectivity: kinetic and thermodynamic control. Single and double asymmetric induction. Glossary of stereochemical terms. References. Analytical Methods. The importance of analysis, and which method to choose. Polarimetry, the old fashioned way. Nuclear magnetic resonance. Chromatography. Summary. References. Enolate, Azaenolate, and Organolithium Alkylations. Enolates and azaenolates. Chiral organolithiums. References. 1,2 and 1,4 Additions to Carbonyls. Cram's rule: open-chain model. Cram's rule: rigid, chelate, or cyclic model. Additions using chiral catalysts or chiral nucleophiles. Conjugate additions. References. Aldol and Michael Additions of Allyls and Enolates. 1,2-Additions of allyl metals and metalloids. Aldol additions. Michael additions. References. Rearrangements and Cycloadditions. Rearrangements. Cycloadditions. References. Reductions and Hydroborations. Reduction of carbon-heteroatom double bonds. Reduction of carbon-carbon bonds. Hydroborations. References. Oxidations. Introduction and scope. Epoxidation and related reactions. Dihydroxylations. Oxidation of enolates and enol ethers. Miscellaneous oxidations. References. Index.

ChemInform Abstract: 1‐Magnesiotetrahydroisoquinolyloxazolines as Chiral Nucleophiles in Stereoselective Additions to Aldehydes: Auxiliary Optimization, Asymmetric Synthesis of (+)‐Corlumine, (+)‐Bicuculline, (+)‐Egenine, and (+)‐Corytensine, and Preliminary 13C NMR Studies of 1‐Lithio‐ and 1‐Magnesiotetrahydroisoquinolyloxazolines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Chiral auxiliaries, ligands and arene chromium complexes

Abstract