Fourth-generation methods

A New Synthesis of Napelline.—Workers at New Brunswick have reported an excellent stereospecific synthesis of napelline (70), based on their fourth generation methods that were developed in the synthesis of several delphinine-type alkaloids.59 These methods had previously been explored with model compounds, and employ the rearrangement of a denudatine system to a napelline system.60 The starting material (123) for this synthesis was prepared by the route analogous to that used for the preparation of 13-deoxydeIphonine.60,61... 

There are essentially four methods of generating chirality, These are frequently referred to as first, second, third, and fourth generation methods ... 

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 each of the previously mentioned three classes, an enantiomerically pure compound has been required in stoichiometric amounts, although in some cases it could be recovered for reuse. The final refinement, possible in the fourth-generation methods, is to use a chiral catalyst to direct the conversion of an achiral substrate directly to a chiral product with an achiral reagent. Again the control here is inter-molecular ... 

This class of reaction, which includes many enzyme-catalysed transformations, is obviously very attractive and is the subject of intensive research at the present time. By definition the catalyst can be recovered unchanged at the end of the reaction and in many cases only a small quantity (0.05 equiv. or less) is required, although this is not always the case and a larger quantity may have to be used, either to achieve a reasonable rate of conversion or to account for losses due to side reactions. The possibility of using only a catalytic amount of enantiomerically pure compound obviously has great attractions for large-scale industrial use where cost is critical. A detailed discussion of third- and fourth-generation methods is the subject of chapter 6. 

An important development in recent years has been the introduction of more sophisticated methods which, on the face of it, combine elements of the first-, second-, third- and fourth-generation methods described in the last section. Thus we can, for example, react a chiral substrate with a chiral reagent. This approach, pioneered by Masamune,Pi is described as multiple asymmetric induction and is particularly valuable in reactions where two new stereogenic units are formed simultaneously. In the example which follows, the aldol reaction between chiral aldehyde (51) and a boron enolate to give (53) and (54) is considered. As it stands this is a first-generation method since the chiral substrate (51) reacts with the achiral enolate to give... 

Third- and fourth-generation methods asymmetric reagents and catalysts... 

We discuss in this chapter some third- and fourth-generation methods of asymmetric synthesis. As the reader will recall, these are distinguished from the first- and second-generation methods by the fact that the asymmetry derives from a reagent or catalyst, rather than from the starting material or a chiral auxiliary. 

THIRD- AND FOURTH-GENERATION METHODS 6.1.2 Asymmetric Michael reaction... 

Regarded by many as one of the most important advances of the 1980s, the Katsuki-Sharpless asymmetric epoxidation is apowerful fourth-generation method of synthesising epoxylalcohols, which are versatile intermediates, with predictable absolute conriguration and very high enantiomeric excess. 

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