Nucleophiles asymmetric synthesis

Palladium-Catalyzed Allylic Alkylation of Sulfur and Oxygen Nucleophiles -Asymmetric Synthesis, Kinetic Resolution and Dynamic Kinetic Resolution... 

Gais H, Jagusch T, Spalthoff N, Gerhards F, Frank M, Raabe G. Highly selective palladium catalyzed kinetic resolution and enantioselective substitution of racemic allylic carbonates with sulfur nucleophiles asymmetric synthesis of allylic sulfides, allylic sulfones, and allylic alcohols. Chem. Eur. J. 2003 9 4202-A221. 

In recent years there has been a proliferation of new reactions and reagents that have been so useful in organic synthesis that often people refer to them by name. Many of these are stereoselective or regioselecth/e methods. While the expert may know exactly what the Makosza vicarious nucleophilic substitution, or the Meyers asymmetric synthesis refers to, many students as well as researchers would appreciate guidance regarding such "Name Reactions". 

Without question, the most significant advance in the use of sulfur-centered nucleophiles was made by Shibasaki, who discovered that 10 mol% of a novel gallium-lithium-bis(binaphthoxide) complex 5 could catalyze the addition of tert-butylthiol to various cyclic and acyclic meso-epoxides with excellent enantioselectiv-ities and in good yields (Scheme 7.11) [21], This work builds on Shibasaki s broader studies of heterobimetallic complexes, in which dual activation of both the electrophile and the nucleophile is invoked [22]. This method has been applied to an efficient asymmetric synthesis of the prostaglandin core through an oxidation/ elimination sequence (Scheme 7.12). 

Analogous results were obtained for enol ether bromination. The reaction of ring-substituted a-methoxy-styrenes (ref. 12) and ethoxyvinylethers (ref. 10), for example, leads to solvent-incorporated products in which only methanol attacks the carbon atom bearing the ether substituent. A nice application of these high regio-and chemoselectivities is found in the synthesis of optically active 2-alkylalkanoic acids (ref. 13). The key step of this asymmetric synthesis is the regioselective and chemoselective bromination of the enol ether 4 in which the chiral inductor is tartaric acid, one of the alcohol functions of which acts as an internal nucleophile (eqn. 2). 

Nguyen HV, Butler DCD, Richards CJ (2006) A metallocene-pyrrolidinopyridine nucleophilic catalyst for asymmetric synthesis. Org Lett 8 769-772... 

Wilson JE, Fu GC (2004) Asymmetric synthesis of highly substituted P-lactones by nucleophile-catalyzed [2 -t 2] cycloadditions of disubstituted ketenes with aldehydes. Angew Chem Int Ed 43 6358-6360... 

Sulfoximines bearing a chiral sulfur atom have recently emerged as valuable ligands for metal-catalysed asymmetric synthesis.In particular, C2-symmetric bis(sulfoximines), such as those depicted in Scheme 1.51, were applied to the test reaction, achieving enantioselectivities of up to 93% ee. The most selective ligand (R = c-Pent, R = Ph) of the series was also applied to the nucleophilic substitution reaction of l,3-diphenyl-2-propenyl acetate with substituted malonates, such as acetamido-derived diethylmalonate, which provided the corresponding product in 89% yield and 98% ee. 

Nucleophilic addition of metal alkyls to carbonyl compounds in the presence of a chiral catalyst has been one of the most extensively explored reactions in asymmetric synthesis. Various chiral amino alcohols as well as diamines with C2 symmetry have been developed as excellent chiral ligands in the enantiose-lective catalytic alkylation of aldehydes with organozincs. Although dialkylzinc compounds are inert to ordinary carbonyl substrates, certain additives can be used to enhance their reactivity. Particularly noteworthy is the finding by Oguni and Omi103 that a small amount of (S)-leucinol catalyzes the reaction of diethylzinc to form (R)-l-phenyl-1 -propanol in 49% ee. This is a case where the... 

Scheme 7-25. Asymmetric synthesis of the chiral co-side chain through chiral ligand-induced nucleophilic addition.

As a kind of nucleophilic addition reaction similar to the Grignard reaction, the Reformatsky reaction can afford useful ft-hydroxy esters from alkyl haloacetate, zinc, and aldehydes or ketones. Indeed, this reaction may complement the aldol reaction for asymmetric synthesis of //-hydroxy esters. 

Asymmetric synthesis of amino acids.1 These lactones can serve as an optically active form of glycine for synthesis of either D- or L-amino acids. Thus (+ )-1 (or (—)-l) on radical bromination is converted into a single monobromide (2), which can be coupled with nucleophilic organometallic reagents, by either an SN1... 

It is of some historical interest that Kiliani s cyanohydrin synthesis (24) enabled Emil Fischer (25) to carry out the first asymmetric synthesis. Lapworth (26) used this base-catalyzed nucleophilic 1,2-addition reaction in one of the first studies of a reaction mechanism. Bredig (27,28) appears to have been the first to use quinine (29) in this reaction as the chiral basic catalyst. More recently, others (20) have used basic polymers to catalyze the addition of cyanide to aldehydes. The structure of quinine has been known since 1908 (30). Yet it is of critical importance that Prelog s seminal work on the mechanism of this asymmetric transformation (eq. [4]) could not have begun (16) until the configuration of quinine was established in 1944 (31,32). 

However, the major factor stimulating the rapid development of static and dynamic sulfur stereochemistry was the interest in the mechanism and steric course of nucleophilic substitution reactions at chiral sulfur. Very recently, chiral organic sulfur compounds have attracted much attention as useful and efficient reagents in asymmetric synthesis. 

Finally, it should be noted that in contrast to optically labile sulfonium ylides, the oxosulfonium yUdes derived from chiral sulfoximides and related compounds are configurationally stable. Johnson and co-workers (184) have obtained a large number of chiral oxosulfonium ylides having the general structures 161 and 162 and have used them as nucleophilic alkylidene transfer agents for asymmetric synthesis. These results are discussed in the last part of this chapter. 

We hope that this review of chiral sulfur compounds will be useful to chemists interested in various aspects of chemistry and stereochemistry. The facts and problems discussed provide numerous possibilities for the study of additional stereochemical phenomena at sulfur. As a consequence of the extent of recent research on the application of oiganosulfur compounds in synthesis, further developments in the field of sulfur stereochemistry and especially in the area of asymmetric synthesis may be expected. Looking to the future, it may be said that the static and dynamic stereochemistry of tetra- and pentacoordinate trigonal-bipyramidal sulfur compounds will be and should be the subject of further studies. Similarly, more investigations will be needed to clarify the complex nature of nucleophilic substitution at tri- and tetracoordinate sulfur. Finally, we note that this chapter was intended to be illustrative, not exhaustive therefore, we apologize to the authors whose important work could not be included. 

Organosulfur chemistry is presently a particularly dynamic subject area. The stereochemical aspects of this field are surveyed by M. Mikojajczyk and J. Drabowicz. in the fifth chapter, entitled Qural Organosulfur Compounds. The synthesis, resolution, and application of a wide range of chiral sulfur compounds are described as are the determination of absolute configuration and of enantiomeric purity of these substances. A discussion of the dynamic stereochemistry of chiral sulfur compounds including racemization processes follows. Finally, nucleophilic substitution on and reaction of such compounds with electrophiles, their use in asymmetric synthesis, and asymmetric induction in the transfer of chirality from sulfur to other centers is discussed in a chapter that should be of interest to chemists in several disciplines, in particular synthetic and natural product chemistry. 

Epoxides are extremely useful intermediates in organic synthesis since they react with a variety of nucleophiles suffering opening of the epoxide ring with retention or inversion of configuration at the carbon undergoing attack. Thus, the development of highly stereoselective methods for the synthesis of certain chiral epoxides, such as the methods under discussion, has enabled the asymmetric synthesis of a wide variety of 1,2-bifunctional compounds. 

Chiral Lewis acid catalysts are powerful tools for asymmetric synthesis, combining a metal or metaloid central atom with a chiral ligand [1, 2], Such chiral Lewis acids activate electrophiles 1 for a nucleophilic attack. Various metals can be used as the center element (Scheme 1). 

Due to the synthetic and biological importance of amines and a-aminoketones, acids and esters, the introduction of amino functionality into carbon nucleophiles provides a convenient and practical route for their synthesis "In addition, a number of electrophilic amination methodologies have been developed for the asymmetric synthesis of amines and a-aminocarbonyl compounds " ". 

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