Asymmetric Allylic Substitution Reactions Research Articles

Diamidophosphites with isomeric carborane fragments: a comparison of catalytic activity in asymmetric Pd-catalyzed allylic substitution reactions

New chiral diamidophosphite ligands containing electron-donating 9-meta-carborane and electron-withdrawing 1-meta-carborane substituents have been synthesized. The ligand 3a with an electron-donating group demonstrated high enantioselectivity in Pd-catalyzed allylic substitution reactions with C-, S- and N-nucleophiles (up to 98% ee). The isomeric diamidophosphite 3b bearing an electron-withdrawing substituent showed in all cases, moderate-to-poor conversion and lower enantioselectivity.

Enantioselective construction of allylic phosphine oxides through substitution of Morita–Baylis–Hillman carbonates with phosphine oxides

The asymmetric organocatalytic allylic substitution reaction of MBH carbonates with phosphine oxides has been developed. This organocatalytic approach constitutes an easy and efficient method for the direct preparation of allylic phosphine oxides in high enantioselectivities.

Pyranoside Phosphite-Oxazoline Ligand Library: Highly Efficient Modular P,N Ligands for Palladium-Catalyzed Allylic Substitution Reactions. A Study of the Key Palladium Allyl Intermediates

We have screened a library of modular phosphite-oxazoline ligands for asymmetric allylic substitution reactions. The library is efficiently prepared from the commercially available and cheap D -glucosamine. The introduction of a phosphite moiety into the ligand design is highly advantageous for the product outcome. Therefore, this ligand library affords good-to-excellent reaction rates [TOFs up to 600 mol substrate x (mol Pd x h) -1 ] and enantioselectivities (ees up to 99%) and, at the same time, shows a broad scope for mono-, di- and trisubstituted linear hindered and unhindered substrates and cyclic substrates. The NMR studies on the palladium allyl intermediates provide a deeper understanding about the effect of the ligand parameters on the origin of enantioselectivity.

ChemInform Abstract: Asymmetric Hydrogenation and Allylic Substitution Reaction with Novel Chiral Pinene‐Derived N,P‐Ligands.

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Asymmetric hydrogenation and allylic substitution reaction with novel chiral pinene-derived N,P-ligands

A series of new chiral tetrahydroquinoline ligands, derived from chiral α-pinene, were successfully synthesized. Iridium and palladium complexes of these ligands were proven to be efficient catalysts for enantioselective hydrogenation and allylic substitution reactions with moderate to excellent enantioselectivities (90–95% ee) and high yields.

The Allyl Intermediate in Regioselective and Enantioselective Iridium-Catalyzed Asymmetric Allylic Substitution Reactions

The isolation and structural characterization of metallacyclic allyl (2a) and crotyl (2b) iridium complexes are reported. Complexes 2a and 2b are rare examples of iriduim allyl complexes that undergo nucleophilic attack at terminal position, rather than the central position, of the allyl unit. Structures of 2a and 2b were obtained by X-ray diffraction. Nucleophilic attack was observed at the carbon that is bound to iridium trans to phosphorus through a longer Ir-C bond. However, the effect of the trans phosphine ligand on the Ir-C bond lengths was smaller than the effect of the substituent on the allyl group in 2b. The competence of complexes 2a and 2b to be intermediates in the catalytic asymmetric allylic substitutions was evaluated by studying their reactivity toward stabilized carbon and heteroatom nucleophiles and comparing the rates and selectivities to those of the catalytic reactions. The stereoselectivity and regioselectivity of stoichiometric reactions of 2b were similar to those of reactions catalyzed by the previously reported iridium catalysts, supporting their intermediacy in the catalytic reactions. On the basis of the structural data, a model is proposed for the origin of stereoselectivity in iridium-catalyzed asymmetric allylic substitution reactions.

Novel pyridine-phosphite ligands for Pd-catalyzed asymmetric allylic substitution reaction

A series of novel chiral pyridine-phosphite ligands, synthesized from PCl3, chiral BINOL and 4H-quinolyl alcohols, have been successfully applied in the Pd-catalyzed asymmetric allylic substitution reaction, which afforded the substituted products with high enantioselectivities (up to 95% ee).

Air-Stable Iridium Catalyst in Asymmetric Allylic Substitution

The authors report a new iridium catalyst system for the asymmetric allylic substitution reaction, furnishing improved chemoselectivity and comparable yields without the need for ­inert atmosphere. Additional mechanistic insight into precatalyst formation is reported based on ³¹P NMR experiments.

Organic Carbonates as Alternative Solvents for Palladium‐Catalyzed Substitution Reactions

Organic carbonates, such as propylene carbonate, butylene carbonate, and diethyl carbonate, were tested in the Pd-catalyzed asymmetric allylic substitution reactions of rac-1,3-diphenyl-3-acetoxy-prop-1-ene with dimethyl malonate or benzylamine as nucleophiles. Bidentate diphosphanes were used as chiral ligands. The application of monodentate phosphanes capable of self-assembling with the metal was likewise tested. In the substitution reaction with dimethyl malonate, enantioselectivities up to 98% were achieved. In the amination reaction, the chiral product was obtained with up to 83% ee. The results confirm that these "green solvents" can be advantageously used for this catalytic transformation as an alternative to those solvents usually employed which run some risk of being harmful to the environment.

New chiral diamide ligands: synthesis and application in allylic alkylation

A new family of chiral diamide ligands has been designed and synthesised. These ligands have been successfully applied to an asymmetric allylic substitution reaction. A palladium complex of one of the diamide ligands achieved enantioselectivities of up to 93% in the allylic alkylation of 1,3-diphenyl-3-acetoxyprop-1-ene.

Screening of a Phosphite–Phosphoramidite Ligand Library for Palladium‐Catalysed Asymmetric Allylic Substitution Reactions: The Origin of Enantioselectivity

We have designed a new library of readily available, highly modular phosphite-phosphoramidite ligands for asymmetric allylic substitution reactions. They are easily prepared in one step from commercially available chiral 1,2-amino alcohols. The introduction of a phosphoramidite moiety into the ligand design is highly advantageous for the product outcome. This ligand library affords high reaction rates (TOFs of up to 800 mol (mol h)(-1)) and enantioselectivities (ees of up to 99%) and, at the same time, contains a broad range of disubstituted hindered and unhindered substrate types. NMR study of the Pd-pi-allyl intermediates provide a deeper understanding of the effect of the ligand parameters on the origin of enantioselectivity.

An outstanding palladium system containing a C2-symmetrical phosphite ligand for enantioselective allylic substitution processes

The use of efficient Pd systems bearing C(2)-symmetric chiral diphosphite ligands derived from carbohydrates in asymmetric allylic substitution reactions is described here, reaching TOFs > 22 000 h(-1) in allylic alkylation and ca. 400 h(-1) in allylic amination, giving excellent enantioselectivities (ee > 99%) and kinetic resolution of the racemic substrate.

Transition Metal-Catalyzed Asymmetric Reactions Using P-Chirogenic Diaminophosphine Oxides: DIAPHOXs

This review describes the development of a new class of chiral phosphorus ligands: amino acid-derived P-chirogenic diaminophosphine oxides, DIAPHOXs, and their application to several transition metal-catalyzed asymmetric allylic substitution reactions. Pd-catalyzed asymmetric allylic alkylation with cyclic beta-keto esters as prochiral nucleophiles was initially examined using P-chirogenic diaminophosphine oxide 1a, resulting in highly enantioselective construction of quaternary stereocenters. Mechanistic investigations revealed that 1a is activated by N,O-bis(trimethylsilyl)acetamide-induced tautomerization to afford a trivalent diamidophosphite species 13, which functions as the actual ligand. Pd-catalyzed asymmetric allylic substitutions of both acyclic and cyclic substrates were also examined using various nucleophiles such as malonate derivatives, nitromethane, aliphatic amines, and aromatic amines, providing a variety of chiral compounds with good to excellent enantioselectivity. In addition, Ir-catalyzed asymmetric allylic amination and alkylation of terminal allylic carbonates were examined using structurally optimized P-chirogenic diaminophosphine oxides, and the corresponding branched products were obtained in a highly regio- and enantioselective manner. Furthermore, the developed catalytic asymmetric process was successfully applied to the catalytic enantioselective synthesis of biologically active compounds, (R)-preclamol, (R)-baclofen hydrochloride, and (-)-paroxetine.

Copper-catalyzed asymmetric allylic substitution reactions with organozinc and Grignard reagents

Abstract Asymmetric allylic alkylations (AAAs) are among the most powerful C-C bond-forming reactions. We present a brief overview of copper-catalyzed AAAs with organometallic reagents and discuss our own contributions to this field. Work with zinc reagents and phosphoramidite ligands provided a framework for later developments which employ Grignard reagents and ferrocenyl ligands. High yields and excellent regioselectivities and enantioselectivities are achieved. The AAAs may be more general than previously envisioned, in terms of using substrates functionalized with heteroatoms at various positions; heteroatom substituents at the γ-position provide densely functionalized building blocks. These h-AAA reactions rely on the design of appropriate substrates containing heteroatoms and have allowed us to demonstrate viable new approaches toward the synthesis of versatile organic building blocks. We illustrate that the chiral secondary allylic alcohols, primary homo-allylic alcohols and amines can readily be obtained in high enantiomeric purity in a catalytic asymmetric fashion by copper-catalyzed AAAs. Furthermore, we show that manipulation of the terminal olefin provides chiral building blocks where the ee of the starting materials is preserved.

Preparation of Chiral Homoannularly Bridged N,P‐Ferrocenyl Ligands by Intramolecular Coupling of 1,5‐Dilithioferrocenes and Their Application in Asymmetric Allylic Substitution Reactions

AbstractHomoannularly bridged ferrocene 6b was prepared by intramolecular coupling of 1,5‐dilithioferrocene 5b mediated by Fe(acac)3. Dilithioferrocene 5b was prepared by lithium–halogen exchange of the corresponding diiodide, which was prepared by 1,5‐dilithiation of the o‐TMS‐blocked ferrocene and followed by trapping with iodine and removal of the TMS group. Alternatively, 5b could be readily prepared by the reaction of o‐bromophenylferrocene 8 with nBuLi (>2 equiv.). The benzene ring of 6b underwent ortho lithiation with tBuLi, and the resulting lithiated species was trapped with Ph2PCl to produce corresponding aminophosphane 7d. Aminophosphane 13, which has the phosphanyl group on the cyclopentadienyl ring, was prepared by intramolecular coupling of 1,5‐dilithiated PhPPFA 11 mediated by Fe(acac)3. New N,P ligands 7d and 13 were used in the palladium‐catalyzed allylic alkylation and amination of 1,3‐diphenyl‐2‐propenyl acetate (14), and ligand 7d was found to give good yields with enantioselectivities as high as 96 % ee. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

First Chiral Phosphoroamidite‐Phosphite Ligands for Highly Enantioselective and Versatile Pd‐Catalyzed Asymmetric Allylic Substitution Reactions.

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Thioether containing ligands for asymmetric allylic substitution reactions

Abstract This review covers reports in the literature on the use of thioether ligands in Pd-catalysed asymmetric allylic substitution reactions from 1996 to June 2006. In the first section, we will cover the results using (S,S)-homo and (S,S)-heterodonor ligands. In the next section, we will present the results using heterodonor (S,X)-ligands, emphasizing the results obtained with (S,N)- and (S,P)-donor ligands. We also discuss any reported mechanistic aspects according to the allylic substitution results.

Pd‐catalyzed asymmetric allylic substitution reactions using P‐chirogenic diaminophosphine oxides: DIAPHOXs

This paper describes the development of a new class of chiral phosphorus ligand: aspartic acid-derived P-chirogenic diaminophosphine oxides, DIAPHOXs, and their application to several Pd-catalyzed asymmetric allylic substitution reactions. Pd-catalyzed asymmetric allylic alkylation was initially examined in detail using diaminophosphine oxides 1a, resulting in the highly enantioselective construction of quaternary stereocenters. Mechanistic investigations revealed that 1a is activated by N,O-bis(trimethylsilyl)acetamide-induced tautomerization to afford a trivalent diamidophosphite species 12, which functions as the actual ligand. Furthermore, asymmetric allylic amination was examined using Pd-DIAPHOX catalyst systems, providing a variety of chiral allylic amines.

Solid-Phase Synthesis of a Peptide-Based P,S-Ligand System Designed for Generation of Combinatorial Catalyst Libraries

An efficient methodology for the solid-phase synthesis of diverse combinatorial peptide-based P,S-ligand libraries based on a modular approach was developed. Chiral thioethers were introduced into a series of peptide scaffolds using commercially available Fmoc-protected cysteine derivatives, and secondary amines were incorporated into the peptide backbones by reductive alkylation using readily available Fmoc-protected amino aldehydes. Phosphinylation of the secondary amines of the scaffolds, applying two different reagents, yielded two different types of ligands. Subsequent complexation with palladium afforded six- or seven-membered chelates, respectively. The selectivity, in an asymmetric allylic substitution reaction, of the two different types of chelates, derived from the same peptide scaffold, was complementary in all cases studied, affording the product as opposite stereoisomers with up to 60% ee. These results hold great promise for the identification of highly selective catalysts upon screening of larger P,S-based catalyst libraries.

First Chiral Phosphoroamidite-phosphite Ligands for Highly Enantioselective and Versatile Pd-Catalyzed Asymmetric Allylic Substitution Reactions

[reaction: see text] A series of phosphite-phosphoroamidite ligands, derived from readily available d-xylose, has been successfully applied for the first time in the Pd-catalyzed allylic substitution of several substrates with different steric and electronic properties, with high enantioselectivities (ee's up to 98) and activities in standard conditions.