Stereoselectivity limitations

The Peterson reaction has two more advantages over the Wittig reaction 1. it is sometimes less vulnerable to sterical hindrance, and 2. groups, which are susceptible to nucleophilic substitution, are not attacked by silylated carbanions. The introduction of a methylene group into a sterically hindered ketone (R.K. Boeckman, Jr., 1973) and the syntheses of olefins with sulfur, selenium, silicon, or tin substituents (D. Seebach, 1973 B.T. Grdbel, 1974, 1977) illustrate useful applications. The reaction is, however, more limited and time consuming than the Wittig reaction, since metallated silicon derivatives are difficult to synthesize and their reactions are rarely stereoselective (T.H. Chan, 1974 ... 

The formation of g-alkyl-a,g-unsaturated esters by reaction of lithium dialkylcuprates or Grignard reagents in the presence of copper(I) iodide, with g-phenylthio-, > g-acetoxy-g-chloro-, and g-phosphoryloxy-a,g-unsaturated esters has been reported. The principal advantage of the enol phosphate method is the ease and efficiency with which these compounds may be prepared from g-keto esters. A wide variety of cyclic and acyclic g-alkyl-a,g-unsaturated esters has been synthesized from the corresponding g-keto esters. However, the method is limited to primary dialkylcuprates. Acyclic g-keto esters afford (Zl-enol phosphates which undergo stereoselective substitution with lithium dialkylcuprates with predominant retention of stereochemistry (usually > 85-98i )). It is essential that the cuprate coupling reaction of the acyclic enol phosphates be carried out at lower temperatures (-47 to -9a°C) to achieve high stereoselectivity. When combined with they-... 

The high degree of stereoselectivity associated with most syntheses and reactions of oxiranes accounts for the enormous utility of these systems in steroid syntheses. Individual selectivity at various positions in the steroid nucleus necessitates the discussion of a collection of uniquely specific reactions used in the synthesis of steroidal epoxides. The most convenient and generally applicable methods involve the peracid, the alkaline hydrogen peroxide and the halohydrin reactions. Several additional but more limited techniques are also available. 

Dipolar cydoadditions are one of the most useful synthetic methods to make stereochemically defined five-membered heterocydes. Although a variety of dia-stereoselective 1,3-dipolar cydoadditions have been well developed, enantioselec-tive versions are still limited [29]. Nitrones are important 1,3-dipoles that have been the target of catalyzed enantioselective reactions [66]. Three different approaches to catalyzed enantioselective reactions have been taken (1) activation of electron-defident alkenes by a chiral Lewis acid [23-26, 32-34, 67], (2) activation of nitrones in the reaction with ketene acetals [30, 31], and (3) coordination of both nitrones and allylic alcohols on a chiral catalyst [20]. Among these approaches, the dipole/HOMO-controlled reactions of electron-deficient alkenes are especially promising because a variety of combinations between chiral Lewis acids and electron-deficient alkenes have been well investigated in the study of catalyzed enantioselective Diels-Alder reactions. Enantioselectivities in catalyzed nitrone cydoadditions sometimes exceed 90% ee, but the efficiency of catalytic loading remains insufficient. 

The use of catalysts for a Diels-Alder reaction is often not necessary, since in many cases the product is obtained in high yield in a reasonable reaction time. In order to increase the regioselectivity and stereoselectivity (e.g. to obtain a particular endo- or exo-product), Lewis acids as catalysts (e.g. TiCU, AICI3, BF3-etherate) have been successfully employed." The usefulness of strong Lewis acids as catalysts may however be limited, because they may also catalyze polymerization reactions of the reactants. Chiral Lewis acid catalysts are used for catalytic enantioselective Diels-Alder reactions. ... 

Olefins are hydrogenated very easily, unless highly hindered, over a variety of catalysts. With active catalysts, the reaction is apt to be diffusion limited, since hydrogen can be consumed faster than it can be supplied to the catalyst surface. Most problems connected with olefin hydrogenation involve some aspect of regio- or stereoselectivity. Often the course of reduction is influenced greatly by the catalyst, by reaction variables, and by hydrogen availability at the catalyst surface. 

Thus, the allyllithium, -sodium or -potassium derivatives are the ones which are most easily generated (Section D.1.3.3.3.1.1.), but they are of limited value in stereoselective carbonyl addition reactions. Usually these reagents need to be tuned" in their reactivity by metal exchange prior to application in order to achieve high selectivities. 

Of the four components reacting in the Ugi reaction, the isocyanide and the carboxylic acid have only limited influence on the overall stereoselection. For instance, in the synthesis of 13-demethyldysidenin (R)-l and 13-demethylisodysidenin (S)-l from a chiral aldehyde, chiral carboxylic acid, isonitrile and methylamine79. 

The synthesis of an epothilone model system via an alternative C9-C10 disconnection was first examined by Danishefsky in 1997. However, extension of this C9-C10 strategy to a fully functionalized epothilone intermediate was not successful, demonstrating the limitations of RCM with the early catalysts A and B [116]. In 2002, Sinha and Sun disclosed the stereoselective total syntheses of epoA (238a) and epoB (238b) by the RCM of epoxy compounds 242 in the presence of catalyst C (Scheme 50) [117]. The reaction furnished an inconsequential mixture of isomers 243 (E/Z 1 1) in high yield. Subsequent selective hydrogenation of the newly formed double bond followed by deprotection led to epothilones A and B. 

Efficiency and selectivity are the two keywords that better outline the outstanding performances of enzymes. However, in some cases unsatisfactory stereoselectivity of enzymes can be found and, in these cases, the enantiomeric excesses of products are too low for synthetic purposes. In order to overcome this limitation, a number of techniques have been proposed to enhance the selectivity of a given biocatalyst. The net effect pursued by all these protocols is the increase of the difference in activation energy (AAG ) of the two competing diastereomeric enzyme-substrate transition state complexes (Figure 1.1). 

Applications of peroxide formation are underrepresented in chiral synthetic chemistry, most likely owing to the limited stability of such intermediates. Lipoxygenases, as prototype biocatalysts for such reactions, display rather limited substrate specificity. However, interesting functionalizations at allylic positions of unsaturated fatty acids can be realized in high regio- and stereoselectivity, when the enzymatic oxidation is coupled to a chemical or enzymatic reduction process. While early work focused on derivatives of arachidonic acid chemical modifications to the carboxylate moiety are possible, provided that a sufficiently hydrophilic functionality remained. By means of this strategy, chiral diendiols are accessible after hydroperoxide reduction (Scheme 9.12) [103,104]. 

The hydrolysis of acetals and ortho esters is governed hy the stereoelectronic control factor previously discussed (see A and B on p. 427) though the effect can generally be seen only in systems where conformational mobility is limited, especially in cyclic systems. There is evidence for synplanar stereoselection in the... 

In many cases, the racemization of a substrate required for DKR is difficult As an example, the production of optically pure cc-amino acids, which are used as intermediates for pharmaceuticals, cosmetics, and as chiral synfhons in organic chemistry [31], may be discussed. One of the important methods of the synthesis of amino acids is the hydrolysis of the appropriate hydantoins. Racemic 5-substituted hydantoins 15 are easily available from aldehydes using a commonly known synthetic procedure (Scheme 5.10) [32]. In the next step, they are enantioselectively hydrolyzed by d- or L-specific hydantoinase and the resulting N-carbamoyl amino acids 16 are hydrolyzed to optically pure a-amino acid 17 by other enzymes, namely, L- or D-specific carbamoylase. This process was introduced in the 1970s for the production of L-amino acids 17 [33]. For many substrates, the racemization process is too slow and in order to increase its rate enzymes called racemases are used. In processes the three enzymes, racemase, hydantoinase, and carbamoylase, can be used simultaneously this enables the production of a-amino acids without isolation of intermediates and increases the yield and productivity. Unfortunately, the commercial application of this process is limited because it is based on L-selective hydantoin-hydrolyzing enzymes [34, 35]. For production of D-amino acid the enzymes of opposite stereoselectivity are required. A recent study indicates that the inversion of enantioselectivity of hydantoinase, the key enzyme in the... 

Although significant progress in the field of asymmetric hydroformylation has been made, it is limited to a rather narrow substrate scope. An alternative approach to a stereoselective hydroformylation might employ substrate control of a chiral alkenic starting material. Of particular use... 

The formation of the carbocationic intermediate (37), either directly or via an initial it complex, appears to be rate-limiting, and the overall orientation of addition is Markownikov. There is evidence of some ANTI stereoselectivity, but this is not very marked and is dependent on the alkene and on the reaction conditions. 

Whole-cell biotransformations frequently showed insufficient stereoselectivities and/or undesired side reactions because of competing enzymatic activities present in the cells. These side reactions can modify the substrates and/or products. Furthermore, whole-cell biotransformations are limited due to the intrinsic need to grow biomass, which generates its own metabolites that are not related to the biotransformation reactions and, therefore, which need to be removed during the downstream process. Both the cells themselves and the unrelated metabolites produced are impurities that need to be removed after the biotransformation reaction. With isolated enzymes, there are no organism and unrelated metabolites to remove after the biotransformation processes. 

Enantiomerically pure 1-sulfinyl-l,3-butadienes 577 are efficient chiral dienes providing the corresponding Diels-Alder products with high stereoselectivity. However, their use in asymmetric synthesis is limited to highly reactive... 

---