Stereocontrolled Alkylative Construction of Quaternary Carbon Centers

摘要

Here we describe practical methods for the stereocontrolled construction of quaternary carbon centers using pseudoephedrine as a chiral auxiliary. Protocols for the stereodefined formation of a,a-disubstituted enolates of pseudoephedrine amides are presented followed by the implementation of these in diastereose-lective alkylation reactions. Equations 1 and 2 illustrate the finding that the diastereomeric a-methylbutyramides 1 and 2 undergo stereospecific enolization with lithium diisopropylamide (LDA) in the presence of lithium chloride at 0 ℃ to form Z- and E-enolates, respectively, as inferred from ~1H NMR analysis of the corresponding cyclic siloxane derivatives [formed upon trapping at -40 ℃ with dichlorodiisopropylsilane in the presence of 13-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU)]. These observations can be rationalized within the framework of prior analyses of pseudoephedrine amide alkylation reactions, extended here to enolate formation. We propose that in the favored pretransition state assemblies the alkoxide side chain and base are positioned on opposite faces of the incipient enolate, with the α-C-H bond aligned for deprotonation (see Figure 1, which illustrates the proposal for the specific case of substrate 1).