Enantioselective reactions continued

The methods of organic synthesis have continued to advance rapidly and we have made an effort to reflect those advances in this Fifth Edition. Among the broad areas that have seen major developments are enantioselective reactions and transition metal catalysis. Computational chemistry is having an expanding impact on synthetic chemistry by evaluating the energy profiles of mechanisms and providing structural representation of unobservable intermediates and transition states. 

Synthetic activity associated with the carbonyl-ene reaction is extensive. During the past decade, the trend has been to perform these reactions in the presence of a Lewis acid in an enantioselective fashion. Efforts to find a general catalyst that affords homoallylic alcohols in high yields and enantioselectivities are continual. The synthetic utility of this reaction has been validated by its application to the synthesis of a number of natural products (see Section 10.12.6) and many structurally novel motifs that have found a place in drug discovery vide infra). It is the latter application that has resulted in research efforts aimed at large-scale production of carbonyl-ene adducts. 

This review continues from one entitled The Chemistry of a,P-Unsaturated Sulfoxides which was recently published in a monograph of organosulfur chemistry. 1 In addition, the coverage has been extended to include the analogous a,P-unsaturated sulfones. The focus of the present review are recent advances in the chemistry of a,P-unsaturated sulfoxides and sulfones, especially those which have been published since 1993. The synthesis of a,P-unsaturated sulfoxides and sulfones has already been reviewed extensively by Rayner2 and hence will not be covered here. Only the chemistry of vinyl (alkenyl) sulfoxides and sulfones will be considered. The chemistry of other a,P-unsaturated sulfoxides and sulfones such as dienyl, allenyl, and propargyl (alkynyl) sulfoxides and sulfones is beyond the scope of this review. Considerable emphasis has been placed on stereo- and enantioselective reactions, reflecting the current interest in this area. 

The current review is of necessity selective. Over the two year period covered, there has been impressive advances in several areas of P(V) chemistry. For example, biological aspects of quinquevalent phosphorus acids chemistry continue to increase in importance. A wide variety of natural and unnatural phosphates including inositols, lipids, some carbohydrates and their phospho-nates, phosphinates and fluorinated analogues has been synthesized. Special attention has been paid to the synthesis of phosphorus analogues of all types of amino acids and some peptides. Numerous investigations of phosphate ester hydrolysis and related reactions continue to be reported. Interest in approaches to easier detoxification of insecticides continues. A number of new and improved stereoselective synthetic procedures have been elaborated. The importance of enantioselective and dynamic kinetic asymmetric transformations is illustrated in many publications. 

It is worth recalling that the asymmetric cyclopropanation of styrene with ethyl diazoacetate, reported in 1966 by Noyori and co-workers, appears to be the first example of transition metal catalyzed enantioselective reaction in homogeneous phase. This reaction remains a landmark in asymmetric cyclopropanation. On a general standpoint, catalytic asymmetric cyclopropanation continues to attract much attention, due in part to the marked trends toward marketing more and more optically active molecules as the optically pure eutomer. This topic has been much studied in connection, inter alia, with the synthesis of valuable intermediates such as chrysanthemic acid derivatives and cilastatin. The subject has been recently reviewed [17]. 

It was also interesting to observe that the mutant lipase which shows an ee of 81% in the model reaction of the p-nitrophenyl ester displays similar performance if the corresponding ethyl ester is used (80 % ee) [76]. Nevertheless, it was not clear at this stage whether the degree of enantioselectivity would continue to climb in further mutagenesis experiments. 

Several enantioselective reductions that use polymer-supported chiral catalysts have been reported. A maj or advantage of performing enantioselective reactions with polymer-supported catalysts is that their use allows both the recycHng of the catalysts and the easy separation of the low molecular weight chiral products. One of the most attractive methods to carry out asymmetric synthesis is the continuous flow system by using an insoluble, polymeric catalyst. 

III.B.2), complexes with manganese, chromium, as well as second- and third-row transition metal ions (e.g., ruthenium) oxidation reactions with dioxygen alone or with other peroxides (e.g., ferf-butyl-peroxide) the stabilization and spectroscopic characterization of mononuclear superoxo, peroxo, and oxo complexes other catalytic processes (e.g., the iron-catalyzed aziridination), enantioselective reactions with chiral bispidine ligands and the iron oxidation chemistry continues to produce novel and exciting results. 

Asymmetric and enantioselective olefination reactions continue to be of interest. Wadsworth-Emmons reactions of 4-substituted cyclohexanones with the phosphonate (147), which carries a chiral benzopyrano-isoxazolidine substituent, proceed with diastereomeric excesses of 80-90% and hence provide another example of such an approach to enantiomerically pure, axially dissymmetric cyclohexylidene derivatives. A further example of trapping of in situ generated ketenes by Wadsworth-Emmons reactions to give allene carboxylates has been reported and the reaction has been extended to enantioselective synthesis by use of the optically active phosphonates (148) (Scheme 14). Moderate to good chemical yields and e.e. values up to 84% were obtained depending on the nature of (148) and the reactions conditions. 

Research into the mechanism of the Heck reaction continues and the understanding of the reaction is increasing. Recent research has revealed that in some intramolecular cases another mechanism is observed. Cationic intermediate 68 can be accessed by associative displacement via the pentacoordinate intermediate 70, leading to high enantioselectivity from a reaction that might be thought to proceed via a neutral pathway. Other studies have also identified key roles for pentacoordinate intermediates as well as anionic complexes.f ... 

Numerous investigations of highly enantioselective reactions catalyzed by chiral phosphoric acids (86) continue to be reported. The potential of this type of Bronsted acid in asymmetric catalysis has been demonstrated. The first asymmetric direct hetero Diels-Alder reaction catalyzed by a chiral Bronsted acid has been described. Thus chiral phosphoric acid (86) exhibited superior enantioselectivity, affording fairly good yields and enantioselectivities for reactions of aromatic aldimines with cyclohexenone (Scheme 21). ... 

This microreactor enabled a highly enantioselective reaction for a racemic amino acid derivative. The integration of enzyme microreactor (CLEA-CEM) and microextractor provided efficient continuous production of optically pure amino acids. 

Since then, researchers have continuously refined the scope of the reaction. In the 1970 s and 1980 s the focus was to understand the stereochemical issues associated with the reaction. Researchers then gradually turned their attention to asymmetric Lewis acids, catalytic reactions, catalytic and enantioselective reactions, reactions catalyzed by Lewis bases, and reactions that can be performed in aqueous solvents. 

This gives chapter an overview of natural cinchona alkaloids and synthetic derivatives together with examples of their use in asymmetric organocatalysis. In recent years, the emphasis has been on the development of cinchona-based bifunctional catalysts, in particular species with a thiourea moiety. The search for new cinchona-based organocatalysts continues and new derivatives are relentlessly being prepared and applied for specific enantioselective reactions. The design of these new... 

Carbonyl ylides continue to be targets of opportunity because of their suitability for trapping by dipolar addition. High enantiocontrol has been achieved in the process described by Eq. 16 [109], but such high enantioselectivity is not general [110] and is dependent on those factors suggested by Scheme 11. Using achiral dirhodium(II) catalysts, Padwa and coworkers have developed a broad selection of tandem reactions of which that in Eq. 17 is illustrative [111] these... 

Imidazole and its derivatives continued to play an important role in asymmetric processes. Optically active pyrroloimidazoles 26 were prepared by the cycloaddition of homochiral imidazolium ylides with activated alkenes <96TL1707>. This reaction was used in the enantioselective preparation of pyrrolidines <96TL1711>. A review of the use of chiral imidazolidines in asymmetric synthesis was published <96PAC531> and the preparation and use of a new camphor-derived imidazolidinone-type auxiliary 27 was reported < 6TL4565> <96TL6931>. 

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