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Biologically active natural products often contain particularly challenging structural features and functionalities. Perhaps foremost among these difficulties are issues of stereochemistry. A useful strategy for synthesizing these molecules is to devise novel methods of bond-formation that provide new opportunities for enantioselective catalysis. In using this tactic, target structures define the problems to be solved and ultimately drive development of catalysis forward. New enantioselective methods discovered in the context of these total synthesis efforts then contribute to a greater understanding of fundamental bond construction and lead to valuable synthetic technologies useful for a variety of other applications.Inasmuch as retrosynthetic analysis 1 enables synthetic planning toward valuable chemical substances, one can be easily discouraged by a lack of methods to install particular functionalities or structural motifs present in the target molecule. Still more difficult is adapting a strategic approach to incorporate the relatively limited number of catalytic enantioselective transformations to allow preparation of enantioenriched materials for further studies. 2,3,4,5, 6 However, when encountering the structural challenges presented by important natural products and pharmaceutical compounds a fruitful strategy is to design a synthesis that hinges upon a particular bond disconnection that is beyond the present lexicon of enantioselective transformations. Employing this strategy, the structures of target molecules provide the impetus for the development of novel transformations and lead to a greater fundamental understanding of methods of bond construction and catalysis. In this Review several recent examples of novel catalytic enantioselective transformations demonstrate the effectiveness of this useful strategy for the preparation of important structural motifs found in biologically active molecules. Each example has contributed not only an effective means of accessing a particular target structure, but also a useful new tool for a variety of further applications in synthetic chemistry.To provide an overview of established catalytic enantioselective methods developed in the context of total synthesis, several notable examples are highlighted in Figure 1. In each of these cases, the target molecules posed particular challenges that had not yet been solved by enantioselective catalysis. Although in some instances (e.g., Diels-Alder reaction, Figure 1a) the methods were developed before their first applications in total synthesis, but the demonstrated value of the transformation served to further highlight the need for enantioselective variants. Subsequent to the development of the [4 + 2] cycloaddition by Diels and Alder in the 1920s, 7 many studies of this transformation elucidated several key facets of Correspondence should be addressed to B.M.S. (email: stoltz@caltech.edu).. † These authors contributed equally to this manuscript.The authors declare no competing financial interests. NIH Public ...

α-Quaternary ketones are accessed through novel enantioselective alkylations of allyl and propargyl electrophiles by unstabilized prochiral enolate nucleophiles in the presence of palladium complexes with various phosphinooxazoline (PHOX) ligands. Excellent yields and high enantiomeric excesses are obtained from three classes of enolate precursors: enol carbonates, enol silanes, and racemic β-ketoesters. Each of these substrate classes functions with nearly identical efficiency in terms of yield and enantioselectivity. Catalyst discovery and development, the optimization of reaction conditions, the exploration of reaction scope, and applications in target-directed synthesis are reported. Experimental observations suggest that these alkylation reactions occur through an unusual inner-sphere mechanism involving binding of the prochiral enolate nucleophile directly to the palladium center.