Geminal dicarboxylates as carbonyl surrogates for asymmetric synthesis. Part I. Asymmetric addition of malonate nucleophiles.

Asymmetric alkylations of allylic geminal dicarboxylates with dialkyl malonates have been investigated. The requisite allylic geminal dicarboxylates are prepared in good yields and high isomeric purities by two catalytic methods, ferric chloride-catalyzed addition of acid anhydrides to alpha,beta-unsaturated aldehydes and palladium-catalyzed isomerization and addition reactions of propargylic acetates. The complex of palladium(0) and the chiral ligand derived from the diamide of trans-1,2-diaminocyclohexane and 2-diphenylphosphinobenzoic acid most efficiently catalyzed the asymmetric process to provide allylic carboxylate esters with high ee. By systematic optimization studies, factors affecting the enantioselectivity of the reaction have been probed. In general, higher ee's have been achieved with those conditions which facilitate kinetic capture of the incipient pi-allylpalladium intermediate. These conditions also proved effective for achieving high regioselectivities. The minor regioisomeric product was formed when reactive substrates or achiral ligands were employed for the reaction, and could be minimized through the use of the chiral ligand. Under the established conditions, the alkylation of various gem-dicarboxylates afforded monoalkylated products in high yields with greater than 90% ee. The process constitutes the equivalent of an addition of a stabilized nucleophile to a carbonyl group with high asymmetric induction.     

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 synthesis of chiral allylic esters

The complex derived from Taniaphos ligand 4 and CuBr*Me2S catalyzes the asymmetric addition of Grignard reagents to 3-bromopropenyl esters 1 to provide allylic esters 2 in high yields and high chemio-, regio-, and enantioselectivities. The work demonstrates that allylic asymmetric alkylation (AAA) can be done on substrates bearing a heteroatom at the gamma-position. The method is a practical route to chiral, nonracemic allylic alcohols. The use of functionalized substrates 1 or Grignard reagents leads to more complex products 2, which can be further manipulated as demonstrated in conversion to (S)-5-ethyl-2(5H)-furanone 6 and (S)-benzoic acid-cyclopent-2-enyl ester 7.     

Cu(I)-catalyzed, α-selective, allylic alkylation reactions between phosphorothioate esters and organomagnesium reagents

Regiocontrol of allylic alkylation reactions involving hard nucleophiles remains a significant challenge and continues to be an active area of research. The lack of general methods in which α-alkylation is favored underscores the need for the development of new processes for achieving this type of selectivity. We report that Cu(I) catalyzes the allylic substitution of phosphorothioate esters with excellent α-regioselectivity, regardless of the nature of the Grignard reagent that is used. To the best of our knowledge, the Cu-catalyzed allylic alkylation of phosphorothioate esters has never been described. We have also developed a simple protocol for inducing high α selectivity starting from secondary allylic halides. This is accomplished by using sodium phosphorothioates as an additive.     

The palladium catalyzed asymmetric addition of oxindoles and allenes: an atom-economical versatile method for the construction of chiral indole alkaloids

The Pd-catalyzed asymmetric allylic alkylation (AAA) is one of the most useful and versatile methods for asymmetric synthesis known in organometallic chemistry. Development of this reaction over the past 30 years has typically relied on the use of an allylic electrophile bearing an appropriate leaving group to access the reactive Pd(π-allyl) intermediate that goes on to the desired coupling product after attack by the nucleophile present in the reaction. Our group has been interested in developing alternative approaches to access the reactive Pd(π-allyl) intermediate that does not require the use of an activated electrophile, which ultimately generates a stoichiometric byproduct in the reaction that is derived from the leftover leaving group. Along these lines, we have demonstrated that allenes can be used to generate the reactive Pd(π-allyl) intermediate in the presence of an acid cocatalyst, and this system is compatible with nucleophiles to allow for formation of formal AAA products by Pd-catalyzed additions to allenes. This article describes our work regarding the use of oxindoles as carbon-based nucleophiles in a Pd-catalyzed asymmetric addition of oxindoles to allenes (Pd-catalyzed hydrocarbonation of allenes). By using the chiral standard Trost ligand (L1) and 3-aryloxindoles as nucleophiles, this hydrocarbonation reaction provides products with two vicinal stereocenters, with one being quaternary, in excellent chemo-, regio-, diastereo-, and enantioselectivities in high chemical yields.     

Effective synthesis of bicyclodienes via palladium-catalyzed asymmetric allylic alkylation and ruthenium-catalyzed cycloisomerization

[n.3.0]Bicycles (n = 3–6) can be synthesized using palladium-catalyzed asymmetric allylic alkylation followed by ruthenium-catalyzed cycloisomerization. New types of triarylphosphino-1,2-diaminooxazoline ligands show the same high levels of enantioselectivity observed with Trost ligand when employed in Pd-catalyzed allylic alkylation reactions. The enyne products of these allylic alkylation reactions were further elaborated using a Ru-catalyzed redox isomerization process, for which a mechanism is proposed.     

Palladium-catalyzed asymmetric allylic alkylation of electron-deficient pyrroles with meso electrophiles

Pyrroles can serve as competent nucleophiles with meso electrophiles in the Pd-catalyzed asymmetric allylic alkylation. The products from this transformation were obtained as a single regio- and diastereomer in high yield and enantiopurity. A nitropyrrole-containing nucleoside analogue was synthesized in seven steps to demonstrate the synthetic utility of this transformation.     

Stereodivergent Desymmetrization of Simple Dicarboxylates via Branch-Selective Pd/Cu Catalyzed Allylic Substitution

Asymmetric desymmetrization has been demonstrated to be a powerful strategy for building stereocenters in asymmetric synthesis. Herein, a Pd/Cu catalyzed asymmetric desymmetrization reaction with a simple geminal dicarboxylate is reported. A wide scope of imino esters bearing an aryl or heteroaromatic group were compatible with this bimetallic catalytic system. The reactions proceeded smoothly, giving the desired products in good yields with high to excellent regio-, diastereo-, and enantioselectivity (up to 20 : 1 branched:linear, >20 : 1 dr, >99 % ee). Notably, the reaction favored branched selectivity, which is unusual for the Pd-catalyzed allylic alkylation reaction. In addition, the standard product could be easily transformed to other valuable molecules such as chiral allylic alcohols, carbamates, and organic boron compounds. Furthermore, DFT calculations were conducted to explain the origin of the branched selectivity.     

1-Phosphino-2-sulfenylferrocenes as planar chiral ligands in enantioselective palladium-catalyzed allylic substitutions

The synthesis of a wide structural variety of enantiopure 1-phosphino-2-sulfenylferrocene ligands 1 possessing exclusively planar chirality is described. In the case of the readily available tert-butylsulfenyl derivatives very high enantioselectivities were obtained in the palladium-catalyzed allylic substitution of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate (ee's up to 97%) and nitrogen nucleophiles (ee's up to 99.5%). Palladium complexes of these ferrocenes were characterized by NMR and X-ray diffraction, revealing the P,S-bidentate character of the ligands 1 and the formation of a single epimer on the stereogenic sulfur atom resulting from the complexation with palladium. A model justifying the observed asymmetric induction exerted by this novel family of chiral ferrocenes, supported by solution NMR studies on a palladium allylic complex, is discussed.     

Synthesis of α-amino acids using transition metal catalysis - alkylation of schiff bases derived from α-amimo acid esters (regio,stereo - selectivity)

A general approach to the synthesis of γ,δ-unsaturated α-amino acid esters is described. Schiff bases derived from glycine and alanine esters were alkylated in the presence of palladium or molybdenum catalysts under neutral or basic conditions using allylic carbonates, esters or halides, (20–95% yield). These less stabilized nucleophiles reacted with the η³ allyl species on the side opposite to the palladium and they can be classified as soft nucleophiles. The regioselectivity was studied with various unsymmetrical electrophiles. After hydrolysis, several functionalized α-amino acids of biological interest (enzymes inhibitors) were obtained. Asymmetric palladium allylic alkylation of the benzophenone imine glycine methyl ester using Pd(OAc)₂ + (+)DIOP was achieved with up to 68 % ee ; the enantioselective Pd-promoted alkylation of this new and useful prochiral nucleophile for the synthesis of α-amino acids is one of the highest ee known.     

Asymmetric Conjugate Additions and Allylic Alkylations Using Nucleophiles Generated by Hydro‐ or Carbometallation

This Minireview discusses catalytic asymmetric conjugate addition and allylic alkylation reactions where the nucleophiles were generated in situ by hydrometallation or carbometallation. This exciting recent trend in asymmetric catalysis promises to expand the range of transformations available for the rapid and selective assembly of complex, functional molecules for both academic and industrial research. This Minireview aims to serve as a reference for studies reported to date and discusses the current state‐of‐the‐art, scope and limitations of these processes.     

Modification of optically active ferrocenylphosphine ligands for palladium-catalyzed asymmetric allylic alkylation

Optically active ferrocenylphosphines containing a functional group on the side chain were effective as ligands for the palladium—catalyzed asymmetric allylic alkylation of 1,3-disubstituted allyl acetates such as l,3-diphenyl-3-acetoxy-l-propene with sodium acetylacetonate and related soft carbon nucleophiles to give the alkylation products of up to 92% ee.     

Annulative Allylic Alkylation Reactions between Dual Electrophiles and Dual Nucleophiles: Applications in Complex Molecule Synthesis

Metal-catalyzed allylic alkylation reactions between dual nucleophiles and dual electrophiles represent a powerful set of methods for the synthesis of small-, medium-, and even large-sized rings. Using this strategy, a handful of simple allylic diol derivatives can be transformed into a broad array of complex carbo- and heterocycles of varying ring sizes in just a single step. Because of their ability to rapidly generate complexity, annulative allylic alkylation reactions between dual nucleophiles and dual electrophiles have been extensively employed in the total synthesis of both natural products and pharmaceutical compounds.     

Selective Benzylic and Allylic Alkylation of Protic Nucleophiles with Sulfonamides through Double Lewis Acid Catalyzed Cleavage of sp3 Carbon–Nitrogen Bonds

The acid‐catalyzed benzylic and allylic alkylation of protic nucleophiles is fundamentally important for the formation of carbon? carbon and carbon? heteroatom bonds, and it is a formidable challenge for benzylic and allylic amine derivatives to be used as the alkylating agents. Herein we report a highly efficient benzylic and allylic alkylation of protic carbon and sulfur nucleophiles with sulfonamides through double Lewis acid catalyzed cleavage of sp³ carbon–nitrogen bonds at room temperature. In the presence of a catalytic amount of inexpensive ZnCl₂‐TMSCl (TMSCl: chlorotrimethylsilane), 1,3‐diketones, β‐keto esters, β‐keto amides, malononitrile, aromatic compounds, thiols, and thioacetic acid can couple with a broad range of tosyl‐activated benzylic and allylic amines to give diversely functionalized products in good to excellent yields and with high regioselectivity. Furthermore, the cross‐coupling reaction of 1,3‐dicarbonyl compounds with benzylic propargylic amine derivatives has been successfully applied to the one‐step synthesis of polysubstituted furans and benzofurans.     

Enantioconvergent synthesis by sequential asymmetric Horner-Wadsworth-Emmons and palladium-catalyzed allylic substitution reactions

A new method for enantioconvergent synthesis has been developed. The strategy relies on the combination of an asymmetric Horner-Wadsworth-Emmons (HWE) reaction and a palladium-catalyzed allylic substitution. Different alpha-oxygen-substituted, racemic aldehydes were initially transformed by asymmetric HWE reactions into mixtures of two major alpha,beta-unsaturated esters, possessing opposite configurations at their allylic stereocenters as well as opposite alkene geometry. Subsequently, these isomeric mixtures of alkenes could be subjected to palladium-catalyzed allylic substitution reactions with carbon, nitrogen, and oxygen nucleophiles. In this latter step, the respective (E) and (Z) alkene substrate isomers were observed to react with opposite stereospecificity: the (E) alkene reacted with retention and the (Z) alkene with inversion of stereochemistry with respect to both the allylic stereocenter and the alkene geometry. Thus, a single gamma-substituted ester was obtained as the overall product, in high isomeric purity. The method was applied to a synthesis of a subunit of the iejimalides, a group of cytotoxic macrolides.     

Regioselective and enantiospecific rhodium-catalyzed allylic alkylation reactions using copper(I) enolates: synthesis of (-)-sugiresinol dimethyl ether

The transition metal-catalyzed allylic alkylation represents a fundamentally important cross-coupling reaction for the construction of ternary carbon stereogenic centers. We have developed a regioselective and enantiospecific rhodium-catalyzed allylic alkylation of acyclic unsymmetrical allylic alcohol derivatives using copper(I) enolates to prepare beta-substituted ketones. This protocol represents a convenient asymmetric Claisen rearrangement surrogate in which alpha-substituted enolates permit the introduction of an additional stereogenic center. The synthetic utility of this transformation was highlighted in the construction of a trans-1,2-disubstituted cyclohexene and the total synthesis of (-)-sugiresinol dimethyl ether. Finally, we anticipate that copper(I) enolates may prove useful nucleophiles in related metal-catalyzed reactions.     

Molybdenum-catalyzed asymmetric allylic alkylation of 3-alkyloxindoles: reaction development and applications

We report a full account of our work towards the development of Mo‐catalyzed asymmetric allylic alkylation reactions with 3‐alkyloxindoles as nucleophiles. The reaction is complementary to the Pd‐catalyzed reaction with regard to the scope of oxindole nucleophiles. A number of 3‐alkyloxindoles were alkylated successfully under mild conditions to give products with excellent yields and good‐to‐excellent enantioselectivities. Applications of this method to the preparation of indoline alkaloids such as (?)‐physostigmine, ent‐(?)‐debromoflustramine B, and the indolinoquinoline rings of communesin B are reported.     

Palladium-catalyzed asymmetric benzylation of 3-aryl oxindoles

Herein we report palladium-catalyzed asymmetric benzylic alkylation with 3-aryl oxindoles as prochiral nucleophiles. Proceeding analogously to asymmetric allylic alkylation, asymmetric benzylation occurs in high yield and enantioselectivity for a variety of unprotected 3-aryl oxindoles and benzylic methyl carbonates using chiral bisphosphine ligands. This methodology represents a novel asymmetric carbon-carbon bond formation between a benzyl group and a prochiral nucleophile to generate a quaternary center.     

靛红Morita-Baylis-Hillman碳酸酯与环状N-磺酰亚胺的不对称烯丙基烷基化反应研究

本课题组近年来发展的通过路易斯碱催化靛红Morita-Baylis-Hillman(MBH)碳酸酯的烯丙基烷基化反应是合成光学纯3,3-二取代2-氧化吲哚化合物的一种有效方法. 在此基础上, 本文研究了手性叔胺催化靛红MBH碳酸酯与环状N-磺酰亚胺的不对称烯丙基烷基化反应, 通过亲电反应途径以较高的立体选择性(达86% ee, dr＞95∶5)和高收率(达96%)合成C-3位含季碳手性中心的多官能团氧化吲哚产物. 通过简单的转化可以得到含多个手性中心的2-吲哚酮-3,4'-哌啶环类骨架, 这为进一步合成生理活性物质研究奠定了基础.     

Recent advances in the application of chiral phosphine ligands in Pd-catalysed asymmetric allylic alkylation

One of the most powerful approaches for the formation of simple and complex chiral molecules is the metal-catalysed asymmetric allylic alkylation. This reaction has been broadly studied with a great variety of substrates and nucleophiles under different reaction conditions and it has promoted the synthesis of new chiral ligands to be evaluated as asymmetric inductors. Although the mechanism as well as the active species equilibria are known, the performance of the catalytic system depends on the fine tuning of factors such as type of substrate, nucleophile nature, reaction medium, catalytic precursor and type of ligand used. Particularly interesting are chiral phosphines which have proved to be effective asymmetric inductors in several such reactions. The present review covers the application of phosphine-donor ligands in Pd-catalysed asymmetric allylic alkylation in the last decade.