Chiral Auxiliaries In Asymmetric Synthesis Research Articles

Asymmetric Synthesis of Trisubstituted Vicinal Diols through Copper(I)‐Catalyzed Diastereoselective and Enantioselective Allylation of Ketones with Siloxypropadienes

AbstractChiral trisubstituted vicinal diols are a type of important organic compounds, serving as both common structure units in bioactive natural products and chiral auxiliaries in asymmetric synthesis. Herein, by using siloxypropadienes as the precursors of allyl copper(I) species, a copper(I)‐catalyzed diastereoselective and enantioselective reductive allylation of ketones was achieved, providing both syn‐diols and anti‐diols in good to excellent enantioselectivity. DFT calculations show that cis‐γ‐siloxy‐allyl copper species are generated favorably with either 1‐TBSO‐propadiene or 1‐TIPSO‐propadiene. Moreover, the steric difference of TBS group and TIPS group distinguishes the face selectivity of acetophenone, leading to syn‐selectivity for 1‐TBSO‐propadiene and anti‐selectivity for 1‐TIPSO‐propadiene. Easy transformations of the products were performed, demonstrating the synthetic utility of the present method. Moreover, one chiral diol prepared in the above transformations was used as a suitable organocatalyst for the catalytic asymmetric reductive self‐coupling of aldimines generated in situ with B2(neo)2.

Asymmetric Synthesis of Trisubstituted Vicinal Diols through Copper(I)-Catalyzed Diastereoselective and Enantioselective Allylation of Ketones with Siloxypropadienes.

Chiral trisubstituted vicinal diols are a type of important organic compounds, serving as both common structure units in bioactive natural products and chiral auxiliaries in asymmetric synthesis. Herein, by using siloxypropadienes as the precursors of allyl copper(I) species, a copper(I)-catalyzed diastereoselective and enantioselective reductive allylation of ketones was achieved, providing both syn-diols and anti-diols in good to excellent enantioselectivity. DFT calculations show that cis-γ-siloxy-allyl copper species are generated favorably with either 1-TBSO-propadiene or 1-TIPSO-propadiene. Moreover, the steric difference of TBS group and TIPS group distinguishes the face selectivity of acetophenone, leading to syn-selectivity for 1-TBSO-propadiene and anti-selectivity for 1-TIPSO-propadiene. Easy transformations of the products were performed, demonstrating the synthetic utility of the present method. Moreover, one chiral diol prepared in the above transformations was used as a suitable organocatalyst for the catalytic asymmetric reductive self-coupling of aldimines generated in situ with B2(neo)2.

The mechanism of cleavage of Evans chiral auxiliaries by LiOOH: origins of the different regioselectivities obtained with LiOH, LiOOH, LiOBn and LiSBn

Oxazolidinones are widely used as chiral auxiliaries in asymmetric synthesis. The chiral auxiliary can be selectively removed using LiOOH, LiOBn or LiSBn, but not LiOH, which instead favours endocyclic cleavage with opening of the oxazolidinone ring. Although Evans originally suggested that the regioselectivity of HO−-mediated hydrolysis may be governed by the relative rates of formation of the two tetrahedral intermediates, whereas the regioselectivity of HOO− cleavage might be determined by their relative breakdown rates, it was not clear why this should be the case. Since then, there appear to have been no mechanistic studies that account for the differing selectivities of LiOH v. LiOOH, and the reason for this difference in selectivity has remained somewhat of an enigma in organic chemistry for many years. Herein, we report DFT computations with M06-2X-D3//B3LYP-D3 to examine the origins of the regioselectivities. The computations predict that all four nucleophiles prefer to attack at the endocyclic carbonyl group, which is less hindered. The barrier for decomposition of the initially formed tetrahedral intermediate determines whether or not the reaction continues all the way to the endocyclic cleavage products. For LiOH, the barrier for decomposition of the intermediate is small and the endocyclic cleavage products are formed. For LiOOH, LiOBn and LiSBn, the decomposition barrier is large, and the exocyclic cleavage pathway instead becomes preferred. An alternative mechanism involving formation of a novel cyclic peroxide intermediate was found to involve a relatively high energy pathway and has been excluded.

Pd-catalyzed functionalization of alkenes and alkynes using removable tethers

The palladium-catalyzed functionalization of alkenes is a versatile transformation in synthetic chemistry, but intermolecular processes often suffer from low reactivity and selectivity. Molecular tethers can be introduced to answer these challenges. They have been used successfully for decades, but their installation and removal normally required multi-step procedures. In this review, we will present progress in this area resulting in more efficient tethering processes. We will start with a brief overview of carbamate- and sulfone-based tethered functionalization of allylic alcohol and amine derivatives. Then the recent development of tethers that can be installed in situ on (homo)-allyl/propargyl amines or alcohols for double and triple bond functionalization will be described. The difunctionalization of alkenes and alkynes using trifluoro acetaldehyde based tethers developed by our group will be covered in more details. Finally, we will introduce the concept of tethers as catalytically formed chiral auxiliaries for asymmetric synthesis.

Glucose - and Allose-Derived Chiral Auxiliaries

Oxazolidinones are an important class of heterocyclic compounds that are used as chiral auxiliaries in asymmetric synthesis and as biologically active pharmaceutical agents. Moreover, carbohydrates are ideal scaffolds to generate libraries of bioactive compounds due the presence of defined configuration. We report here asymmetric alkylation studies on N-derivatized glucose-and allose-based spirooxazolidinones which do act as chiral auxiliaries.

Looking Inside the Intramolecular C-H∙∙∙O Hydrogen Bond in Lactams Derived from α-Methylbenzylamine.

Recently, strong evidence that supports the presence of an intramolecular C−H···O hydrogen bond in amides derived from the chiral auxiliary α-methylbenzylamine was disclosed. Due to the high importance of this chiral auxiliary in asymmetric synthesis, the inadvertent presence of this C−H···O interaction may lead to new interpretations upon stereochemical models in which this chiral auxiliary is present. Therefore, a series of lactams containing the chiral auxiliary α-methylbenzylamine (from three to eight-membered ring) were theoretically studied at the MP2/cc-pVDZ level of theory with the purpose of studying the origin and nature of the C−Hα···O interaction. NBO analysis revealed that rehybridization at C atom of the C−Hα bond (s-character at C is ~23%) and the subsequent bond polarization are the dominant effect over the orbital interaction energy n(O)→σ*C−Hα (E(2) < 2 kcal/mol), causing an important shortening of the C−Hα bond distance and an increment in the positive charge in the Hα atom.

Recent Advances in the Applications of SAMP/RAMP as Chiral Auxiliaries in Asymmetric Synthesis

Nowadays, the stereoselective synthesis of naturally occurring compounds showing biological activity has attracted much attention and stirred up the interest of organic synthetic chemists. Apparently, the multi-step total synthesis of such complex molecules bearing several stereogenic centers demands the development of the efficient and operational strategies for the induction of chirality in a certain step (steps). Among the most practical approaches in the area of stoichiometric asymmetric synthesis, the SAMP/RAMP hydrazone methodology has been found to be a powerful tool in the synthesis of numerous naturally occurring, and bioactive compounds. In this report, we try to highlight the applications of this methodology in asymmetric synthesis. Keywords: Chiral auxiliaries, asymmetric synthesis, SAMP/RAMP, stereoselective synthesis.

Characterization of a novel amine transaminase from Halomonas elongata

Chiral amines are indispensable building blocks in the production of biologically active compounds. They are fundamental for the pharmaceutical industry, both as active molecules themselves and as chiral auxiliaries in asymmetric synthesis; however, the available synthetic strategies often present disadvantages. ω-Transaminases (ω-TAs) appear as an attractive alternative by driving the stereoselective amination of prochiral ketones. HEWT is a novel amine transaminase from the moderate halophilic bacterium, Halomonas elongata DSM 2581, which is highly (S)-selective, being able to fully convert (S)-1-phenylethylamine to acetophenone and showing no activity with the corresponding (R)-1-phenylethylamine. HEWT has a broad substrate scope, active with a range of amino donors and acceptors, and naturally accepts isopropylamine (IPA) as amino donor in asymmetric synthesis providing a 41% conversion of pyruvate in 24h at 37°C starting with 1:1 molar ratio between the reagents. HEWT also accepts ortho-xylylenediamine as amino donor in for amine synthesis, in particular, with benzaldehyde yielding high conversions between 90 and 95%. The enzyme is also tolerant to the presence of cosolvents up to 20% making it a promising candidate for industrial applications.

スルホキシド不斉配位子

Enantiopure sulfoxides are recognized as useful and versatile chiral auxiliaries in asymmetric synthesis. In contrast, much less explored is the use of chiral sulfoxide as ligands for late transition metal catalysts which favorably make sulfur coordination. This article provides a brief overview of the development of such ligands bearing chiral sulfoxide moiety. In 2008, Dorta introduced the highly efficient axially chiral bis-sulfoxide ligands (BINASO) for Rh-catalyzed enantioselective 1,4-addition of arylboronic acids to α,β-unsaturated ketones. After this seminal report, several novel chiral sulfoxide ligands appeared to work for Pd- or Rh-catalyzed asymmetric transformations.

Solid-phase asymmetric synthesis using a polymer-supported chiral Evans'-type oxazolidin-2-one

This protocol describes the synthesis of (S)-4-(4-hydroxybenzyl)-oxazolidin-2-one, its attachment to a Merrifield-Cl resin and its use for asymmetric synthesis. The chiral auxiliary is prepared in four steps from N-Boc-L-tyrosine on a multigram scale in high yield and attached to Merrifield-Cl resin via its phenolic group to afford a solid-supported chiral auxiliary for asymmetric synthesis that takes ∼7 d to prepare. A procedure for its N-acylation is reported and a method for carrying out diastereoselective solid-supported Evans' syn-aldol reactions is described, with aldol products being cleaved from the polymer by either hydrolysis or reduction. The use of the supported auxiliary for two sequential 'on-bead' reactions has been demonstrated for the synthesis of a chiral cyclopropane aldol and a γ-lactone in a >95:5 diastereomeric ratio. These polymer-supported reactions are carried out in IRORI Kan resin capsules to protect the polymer support from mechanical degradation, thus allowing multiple on-bead reactions to be performed.

ChemInform Abstract: 2‐Imidazolidinones as Chiral Auxiliaries in Asymmetric Synthesis

ChemInform Abstract: 2‐Imidazolidinones as Chiral Auxiliaries in Asymmetric Synthesis

2-Imidazolidinones as Chiral Auxiliaries in Asymmetric Synthesis

2-Imidazolidinones as Chiral Auxiliaries in Asymmetric Synthesis

L-Tartaric Acid as a New Chiral Auxiliary for Asymmetric Synthesis of Piperazinones, Morpholinones, Dihydroquinoxalinones and Dihydrobenzoxazinones

E-mail: parkyong@konkuk.ac.krReceived July 19, 2012, Accepted August 10, 2012Key Words : Dynamic resolution, Nucleophilic substitution, Tartaric acid, Chiral auxiliary, Asymmetric syn-thesisDynamic resolution of α-haloacyl compounds in nucleo-philic substitution has been recently developed as an asym-metric synthetic method for α-substituted carboxylic acids.

Pseudoephenamine: A Practical Chiral Auxiliary for Asymmetric Synthesis

Unrestricted: Pseudoephenamine is introduced as a versatile chiral auxiliary and an alternative to pseudoephedrine in asymmetric synthesis. It is free from regulatory restrictions and leads to remarkable stereocontrol in alkylation reactions, especially in those that form quaternary carbon centers. Amides derived from pseudoephenamine exhibit a high propensity to be crystalline substances, and provide sharp, well-defined signals in NMR spectra.

Pseudoephenamine: A Practical Chiral Auxiliary for Asymmetric Synthesis

Uneingeschränkt: Pseudoephenamin wird als vielseitiges chirales Auxiliar und als eine Alternative zu Pseudoephedrin in der asymmetrischen Synthese vorgestellt. Es hat keine regulatorischen Einschränkungen und führt zu bemerkenswerter Stereokontrolle in Alkylierungen, vor allem in solchen, die ein quartäres Kohlenstoffzentrum aufbauen. Aus Pseudoephenamin erhaltene Amide sind meist kristalline Substanzen und ergeben scharfe, gut definierte Signale in ihren NMR-Spektren.

ChemInform Abstract: A Simple Synthesis of (S)‐α,α‐Diaryl‐2‐pyrrolidinemethanols.

The enantiopure α,α-diaryl-2-pyrrolidinemethanols and their derivatives represent an important class of chiral auxiliaries for asymmetric synthesis, including reagents for Corey-Bakshi-Shibata redu...

A Simple Synthesis of (S)-α,α-Diaryl-2-pyrrolidinemethanols

The enantiopure α,α-diaryl-2-pyrrolidinemethanols and their derivatives represent an important class of chiral auxiliaries for asymmetric synthesis, including reagents for Corey-Bakshi-Shibata redu...

An Efficient Synthesis of 1-Acyl-3-arylimidazolidines Catalyzed by Montmorillonite K-10 Clay under Microwave Irradiation

The synthesis of 1-acyl-3-arylimidazolidines were performed by reaction of N-acyl-N -arylethylenediamines with formaldehyde and Montmorillonite clay K-10 as a catalyst under microwave irradiation. INTRODUCTION Tetrahydroimidazoles (imidazolidines) are cyclic aminals of pharmacological interest due to the bioactivity shown by some members which is closely related to the substitution type. The most studied compounds are those N,N -disubstituted ones with alkyl or aryl groups, functionalized sometimes. Accordingly, a large number of these compounds with diverse properties such as strogenic activity and mammary tumor inhibition, anti inflammatory and analgesic activity have been described in the literature. Fungicide, bactericide and antiviral activities had also been reported. On the other hand, due to the hydrophobic nature of imidazolidines they can be used to increase the bioavailability of biologically active precursors in the form of a pro-drug and they had been employed as carriers of pharmacologically active ethylenediamines or carbonyl compounds. They are also closely related to the coenzyme N,N-methylenetetrahydrofolic acid, which participate in single carbon transfer at the oxidation level of formaldehyde. Synthesis and study of this type of compounds present interest from a chemical point of view, as synthetic intermediates of cyclic and acyclic compounds with the ethylenediamine structural unit. Thus, dehydrogenation of imidazolidines leads to 4,5-dihydro-1H-imidazolium salts and their selective reduction to N,N,N -trisubstituted ethylenediamines. The imidazolidine system has been widely employed as protecting group of vicinal diamines in peptide synthesis, due to its easy cleavage in mild acid medium. Besides, imidazolidines were also employed as heterocyclic chiral auxiliaries in asymmetric synthesis. Opposite to compounds HETEROCYCLES, Vol. 78, No. 3, 2009 771

Oxazolidin-2-one Ring, a Popular Framework in Synthetic Organic Chemistry: Part 1. The Construction of the Oxazolidin-2-one Ring

The 1,3-oxazolidin-2-one nucleus is a popular heterocycle framework in synthetic organic chemistry, as well as in medicinal chemistry. This paper deals with the huge number of synthetic approaches addressed to the construction of this five-member ring, with a particular care for the mechanistic and stereochemical outcome. The 2-oxo-1,3-oxazolidine ring is a cyclic carbamate skeleton quite rare in natural product chemistry but very popular in the Synthetic Organic Chemistry since the Evans' report (1) in 1981 on the use of enantiomerically pure 4- substituted oxazolidin-2-ones as chiral auxiliaries in asymmetric synthesis. Oxazolidinones have also a large application as protective groups for the 1,2-aminoalcohol system. Finally, the introduction in the pharmaceutical market of Linezolid (2), an oxazolidin-2-one-based antibacterial drug, attracted the interest of the scientists and resulted in the production of several publications.

Roads to New Guanidine Chemistry from 2‐Imidazolidinones Through 2‐Chloroamidinium Derivatives

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