Enantioselective reactions continued synthesis

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]. 

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. 

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. 

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>. 

It is interesting to note that the oxa-analogous Michael addition was reported for the first time in 1878 by Loydl et al. [19] in their work on the synthesis of artificial malic acid, which was five years ahead of the discovery of the actual Michael reaction described first by Komnenos [20], Claisen [21], and later Michael in 1887 [22] as one of the most important methods for C—C bond formation. In continuation of the early work on the oxa-Michael addition [23], the inter- and intramolecular additions of alkoxides to enantiopure Michael acceptors has been investigated, leading to the diastereo- and enantioselective synthesis of the corresponding Michael adducts [24]. The intramolecular reaction has often been used as a key step in natural product synthesis, for example as by Nicolaou et al. in the synthesis of Brevetoxin B in 1989 [25]. The addition of oxygen nucleophiles to nitro-alkenes was described by Barrett et al. [26], Kamimura et al. [27], and Brade and Vasella [28]. 

Initial preparative work with oxynitrilases in neutral aqueous solution [517, 518] was hampered by the fact that under these reaction conditions the enzymatic addition has to compete with a spontaneous chemical reaction which limits enantioselectivity. Major improvements in optical purity of cyanohydrins were achieved by conducting the addition under acidic conditions to suppress the uncatalyzed side reaction [519], or by switching to a water immiscible organic solvent as the reaction medium [520], preferably diisopropyl ether. For the latter case, the enzymes are readily immobilized by physical adsorption onto cellulose. A continuous process has been developed for chiral cyanohydrin synthesis using an enzyme membrane reactor [61]. Acetone cyanhydrin can replace the highly toxic hydrocyanic acid as the cyanide source [521], Inexpensive defatted almond meal has been found to be a convenient substitute for the purified (R)-oxynitrilase without sacrificing enantioselectivity [522-524], Similarly, lyophilized and powered Sorghum bicolor shoots have been successfully tested as an alternative source for the purified (S)-oxynitrilase [525],... 

One case study within the framework of this project is thus to test the concept of a micro structured reactor plant by applying the fast reaction of the enantioselective synthesis via organoboranes yielding chiral-substituted alcohols. This is typically a batch process carried out in the laboratory using conventional glassware and in the present case has been converted into a continuous process carried out by micro structured devices. This set-up has been used to characterize the physical properties of the backbone system. 

In 2005, Baxendale et al. reported the first enantioselective synthesis of 2-aryl-2,3-dihydro-3-benzofurancarboxamide neolignan (grossamide) 260 conducted under continuous flow conditions. As illustrated in Scheme 73, the first step of the reaction involved the synthesis of amide 261 via the coupling of ferulic acid 262 and tyramine 171, in the presence of PS-HOBt 263. Monitoring reaction progress by LC-MS, the authors were able to optimize this step to afford the amide 261 in 90% conversion however, prior to performing the second reaction step it was imperative to remove any residual tyramine 171. As Scheme 74 illustrates, this was achieved by... 

The use of hDA methodology as a means of constructing the dihydropyran-4-one ring system continues to attract much interest. A review concerning the enantioselective hDA reaction covers the synthesis of dihydropyran-4-ones using this cycloaddition approach <2000AGE3558>. 

Abstract Enantioselection in a stoichiometric or catalytic reaction is governed by small increments of free enthalpy of activation, and such transformations are thus in principle suited to assessing dendrimer effects which result from the immobilization of molecular catalysts. Chiral dendrimer catalysts, which possess a high level of structural regularity, molecular monodispersity and well-defined catalytic sites, have been generated either by attachment of achiral complexes to chiral dendrimer structures or by immobilization of chiral catalysts to non-chiral dendrimers. As monodispersed macromolecular supports they provide ideal model systems for less regularly structured but commercially more viable supports such as hyperbranched polymers, and have been successfully employed in continuous-flow membrane reactors. The combination of an efficient control over the environment of the active sites of multi-functional catalysts and their immobilization on an insoluble macromolecular support has resulted in the synthesis of catalytic dendronized polymers. In these, the catalysts are attached in a well-defined way to the dendritic sections, thus ensuring a well-defined microenvironment which is similar to that of the soluble molecular species or at least closely related to the dendrimer catalysts themselves. 

This type of additive (or ligand) control of stereoselectivity has three advantages. First of all, after the reaction has been completed, the chiral additive can be separated from the product with physical methods, for example, chromatographically. In the second place, the chiral additive is therefore also easier to recover than if it had to be first liberated from the product by means of a chemical reaction. The third advantage of additive control of enantioselectivity is that the enantiomerically pure chiral additive does not necessarily have to be used in stoichiometric amounts catalytic amounts may be sufficient. This type of catalytic asymmetric synthesis, especially on an industrial scale, is important and will continue to be so. 

Sulfoximines are versatile reagents for diastereoselective and asymmetric synthesis. They continue to find many synthetic applications as both nucleophilic and electrophilic reagents. While the nucleophilic character of sulfoximine reagents has been well exploited,1 the use of the sulfoximine group as a nucleofuge is more recent and adds to the synthetic use of these compounds. The palladium(0)-catalyzed chemistry of allylic sulfoximines and the use of chiral sulfoximines as ligands in catalytic asymmetric synthesis are areas of recent development that have potentially useful applications. Further work is required to understand the factors that determine the diastereoselection and the stereochemical outcomes of these reactions. These studies will result in enhanced product diastereo- and enantioselectivities and make these reagents even more attractive to the wider synthetic chemistry community. 

---