Second-generation methods

Although second-generation methods have proved useful, the requirement for two extra steps, namely, the attachment and the removal of the chiral auxiliary, is a cumbersome feature. This is avoided in the third-generation method in which an achiral substrate is directly converted to the chiral product using a chiral reagent (Fig. 1-30, 3). In contrast to the first- and second-generation methods, the stereocontrol is now achieved intermolecularly. 

In Chapter 7 we have already discussed the use of fluorous biphasic systems to facilitate recovery of catalysts that have been derivatized with fluorous ponytails . The relatively high costs of perfluoroalkane solvents coupled with their persistent properties pose serious limitations for their industrial application. Consequently, second generation methods have been directed towards the elimination of the need for perfluoro solvents by exploiting the temperature-dependent solubilities of fluorous catalysts in common organic solvents [42]. Thus, appropriately designed fluorous catalysts are soluble at elevated temperatures and essentially insoluble at lower temperatures, allowing for catalyst recovery by simple filtration. 

One method uses antibodies against PTH(l-4) and even requires the presence of the most N-terminal amino acid, as evidenced by its failure to recognize PTH(2-34). As of 2004, three second generation methods from two manufacturers were listed on the College of American Pathologists Interlaboratory Survey. 

The success of the Second Generation methods soon spawned a number of new algorithms [53-61], each of which sought to improve upon the ones which had preceded it. The primary goal for these Third Generation methods has been maximum computational efficiency and the main driving force behind their development has been the desire to apply rigorous SCF methods to molecular systems with tens, hundreds, or even thousands, of atoms. 

Beller later reported that a dimeric Pd/IMes complex (1) furnishes similar yields, but in a shorter time (typically 1 h), as compared with Pd/PCy3 [33]. Another NHC ligand, IPr, was also investigated, but it was considerably less effective. Entries 6-9 of Table 8 provide a sampling of Kumada-Murahashi reactions that are catalyzed by Pd/IMes. Esters (entry 7) and imides (entry 9) are compatible with this second-generation method. 

Note that in the first and second generation methods, asymmetry derives from the starting material or a chiral auxiliary, whereas in the third and fourth generation methods, it derives from a reagent or a catalyst. All of these methods require inducing chirality (by the substrate, reagent, or catalyst) either at the start or at some point during the synthetic sequence. Enantioselectivity is possible in all of these cases. 

In the first generation of HRA methods, human failure was seen and investigated as random phenomenon, with some distribution in time formed by performance shaping factors influence. In HRA second generation method/framework ATHEANA, treatment of human failure is different, as it is seen as cause based consequence of error forcing context actuation. Still, the plant specific experience can lead to the conclusion that some residual randomness should be kept in hiunan failure model, similarly to the case of (equipment) dependent errors and residual common cause failures. 

Several different measures of the diastereoselectivity can be given. Just as for e.e., we can define the diastereomeric excess (d.e.) of a reaction as the proportion of the major diastereomer produced less that of the minor one. In examples such as the one here, where one new stereogenic unit is formed in a diastereoselective reaction, this is the preferred measure of selectivity. While it does not have the same correlation with optical purity as e.e., it does have the advantage that if the original stereogenic unit(s) are removed, as, for example, by removal of the chiral auxiliary in a second-generation method (see chapter 5), the e.e. of the final product correlates directly with the d.e. of the initial product. Thus if the mixture of (56) and (57) was decarboxylated, the e.e. of the resulting amino alcohol would be equal to the d.e. of (56)/(57). 

In contrast to the first- and second-generation methods, the control is now intermolecular. This is obviously an attractive procedure but the range of reactions for which effective chiral reagents exist is somewhat limited at present. An example is provided by the hydroboration of 1-methylcyclohexene, using isopinocampheyl-borane (40) derived from (+)-a-pinene (31), to give alcohol (41) with two adjacent stereogenic centres. 

First- and second-generation methods chiral starting materials and auxiliaries... 

The bulk of this chapter is concerned with second-generation methods, subdivided according to whether the reactant bearing the chiral auxiliary reacts as a nucleophile, an electrophile, or neither. We begin, however, by considering a few examples of non-stereodifferentiating and first-generation methods. 

Second-generation methods nucleophiles bearing a chiral auxiliary... 

The second-generation methods described in this chapter have been divided into three main groups. In the first, which t e up the rest of this section, the substrate bearing the chiral auxiliary reacts as a nucleophile, in the second (section 5.4) it is electrophilic, and in the third (section 5.5) it is neither. 

The diastereofacial selectivity of an asymmetric aldol reaction can also be controlled on the enolate side, and this is the basis of the second-generation methods of Evanst l and Masamune.l24] The complementary Evans auxiliaries (66) and (67) are synthesised from (5)-valine and (15,2/ )-norephedrine respectively. TheZ-enolate (68) is formed exclusively on reaction with dibutylboron triflate, and this reacts with aldehydes to give essentially only one aldol product (69). The diastereofacial selectivity derives from the bulky groups on the auxiliaries which force attack from the opposite face. 

FIRST- AND SECOND-GENERATION METHODS 5.5 Chiral auxiliaries in concerted reactions... 

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