Nucleophilic substitution, asymmetric

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". 

Chiral pyridine-based ligands were, among various Ar,AT-coordinating ligands, more efficient associated to palladium for asymmetric nucleophilic allylic substitution. Asymmetric molybdenum-catalyzed alkylations, especially of non-symmetric allylic derivatives as substrates, have been very efficiently performed with bis(pyridylamide) ligands. 

Helquist et al. [129] have reported molecular mechanics calculations to predict the suitability of a number of chiral-substituted phenanthrolines and their corresponding palladium-complexes for use in asymmetric nucleophilic substitutions of allylic acetates. Good correlation was obtained with experimental results, the highest levels of asymmetric induction being predicted and obtained with a readily available 2-(2-bornyl)-phenanthroline ligand (90 in Scheme 50). Kocovsky et al. [130] prepared a series of chiral bipyridines, also derived from monoterpene (namely pinocarvone or myrtenal). They synthesized and characterized corresponding Mo complexes, which were found to be moderately enantioselective in allylic substitution (up to 22%). 

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. 

The novel asymmetric nucleophilic substitution to the ketimine was discovered and optimized for this preparation. 

The ANM group was selected as the nitrogen protecting group for the novel asymmetric nucleophilic substitution providing the optimum enantioselectivity. 

Chiral sulfonium ylides have been known for some 30 years, and their stereochemistry and properties have been studied.15 Optically active selenonium ylides were obtained by reacting selenoxides with 1,3-cyclohexanedione under asymmetric conditions by Sakaki and Oae in 1976 for the first time,16 and also optically resolved by fractional recrystallization of the diastereomeric mixtures in the early 1990s.17 In 1995, optically active selenonium ylides 6 were obtained in over 99% de by nucleophilic substitution of optically active chloroselenurane or selenoxide with active methylene compounds with retention of configuration.18 The absolute configurations were determined by X-ray analysis of one... 

Additions to quinoline derivatives also continued to be reported last year. Chiral dihydroquinoline-2-nitriles 55 were prepared in up to 91% ee via a catalytic, asymmetric Reissert-type reaction promoted by a Lewis acid-Lewis base bifunctional catalyst. The dihydroquinoline-2-nitrile derivatives can be converted to tetrahydroquinoline-2-carboxylates without any loss of enantiomeric purity <00JA6327>. In addition the cyanomethyl group was introduced selectively at the C2-position of quinoline derivatives by reaction of trimethylsilylacetonitrile with quinolinium methiodides in the presence of CsF <00JOC907>. The reaction of quinolylmethyl and l-(quinolyl)ethylacetates with dimethylmalonate anion in the presence of Pd(0) was reported. Products of nucleophilic substitution and elimination and reduction products were obtained . Pyridoquinolines were prepared in one step from quinolines and 6-substituted quinolines under Friedel-Crafts conditions <00JCS(P1)2898>. 

In this chapter, we study the variation in the FF during asymmetric stretching and bending in ammonia, internal rotation in H202, and along the intrinsic reaction coordinate (IRC) of three prototypical examples of chemical reactions, viz., (1) a thermoneutral reaction, such as a symmetrical gas-phase SN2 type nucleophilic substitution ... 

Many theories have been put forward to explain the mechanism of inversion. According to the accepted Hugles, Ingold theory aliphatic nucleophilic substitution reactions occur eigher by SN2 or SN1 mechanism. In the SN2 mechanism the backside attack reduces electrostatic repulsion in the transition state to a minimum when the leaving meleophile leaves the asymmetric carbon, naturally an inversion of configuration occurs at the central carbon atom. 

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. 

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. 

Couplings can also be carried out by simple nucleophilic substitution reactions of arenechromium tricarbonyls . For example, in the synthesis of biaryl 469, asymmetric lithiation of 463 using in situ silylation provides the complex 466 via 464 and 465. Nucleophilic substitution by the tolyl Grignard 467 yields 468 as a single atropisomer in 68% yield, and decomplexation gives the biaryl 469 in 92% yield (Scheme 184). 

The formation of chromane derivatives has also been realised in the palladium catalyzed intramolecular nucleophilic substitution of allyl carbonates (Tsuji-Trost reaction). In most cases the reaction is accompanied by the formation of a new centre of chirality. Using Trost s chiral ligand the ring closure was carried out in an enantioselective manner. The asymmetric allylation of the phenol derivative shown in 4.20. was achieved both in good yield and with excellent selectivity.23... 

Some organic reactions can be accomplished by using two-layer systems in which phase-transfer catalysts play an important role (34). The phase-transfer reaction proceeds via ion pairs, and asymmetric induction is expected to emerge when chiral quaternary ammonium salts are used. The ion-pair interaction, however, is usually not strong enough to control the absolute stereochemistry of the reaction (35). Numerous trials have resulted in low or only moderate stereoselectivity, probably because of the loose orientation of the ion-paired intermediates or transition states. These reactions include, but are not limited to, carbene addition to alkenes, reaction of sulfur ylides and aldehydes, nucleophilic substitution of secondary alkyl halides, Darzens reaction, chlorination... 

---