Protocols for the stereodefined formation of α,α-disubstituted enolates of pseudoephedrine amides are presented followed by the implementation of these in diastereoselective alkylation reactions. Direct alkylation of α,α-disubstituted pseudoephedrine amide substrates is demonstrated to be both efficient and diastereoselective across a range of substrates, as exemplified by alkylation of the diastereomeric pseudoephedrine α-methylbutyramides, where both substrates are found to undergo stereospecific replacement of the α-C-H bond with α-C-alkyl, with retention of stereochemistry. This is shown to arise by sequential stereospecific enolization and alkylation reactions, with the alkyl halide attacking a common π-face of the E-and Z-enolates, proposed to be that opposite the pseudoephedrine alkoxide side-chain. Pseudoephedrine α-phenylbutyramides are found to undergo highly stereoselective but not stereospecific α-alkylation reactions, which evidence suggests is due to facile enolate isomerization. Also, we show that α, α-disubstituted pseudoephedrine amide enolates can be generated in a highly stereocontrolled fashion by conjugate addition of an alkyllithium reagent to the s-cis-conformer of an α-alkyl-α,β-unsaturated pseudoephedrine amide, providing α,α-disubstituted enolate substrates that undergo alkylation in the same sense as those formed by direct deprotonation. Methods are presented to transform the α-quaternary pseudoephedrine amide products into optically active carboxylic acids, ketones, primary alcohols, and aldehydes.Here we describe practical methods for the stereocontrolled construction of quaternary carbon centers using pseudoephedrine as a chiral auxiliary. 1-3 Protocols for the stereodefined formation of α,α-disubstituted enolates of pseudoephedrine amides are presented followed by the implementation of these in diastereoselective alkylation reactions.Equations 1 and 2 illustrate the finding that the diastereomeric α-methylbutyramides 1 and 2 undergo stereospecific enolization with lithium diisopropylamide (LDA) in the presence of lithium chloride at 0 °C to form Z-and E-enolates, respectively, as inferred from 1 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript dichlorodiisopropylsilane in the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU)]. 4 These observations can be rationalized within the framework of prior analyses of pseudoephedrine amide alkylation reactions, extended here to enolate formation. 1c-f We propose that in the favored pre-transition 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).(1)Alkylation of enolates derived from amides 1 and 2 at −40 °C, initially examined using an excess of the electrophile benzyl bromide (2 equiv), was also stereospecific; replacement of the α-C-H bond with α-C-benzyl proceeded with net retention of stereochemist...

Here we describe a 5-step sequence to prepare the AB enone 1, the key precursor to fully synthetic tetracyclines, that begins with a diastereoselective Michael–Claisen coupling of two simple starting materials, a cyclohexenone (compound 2 or, in a refinement, a substituted variant, vide infra) and the isoxazole ester 3. This advance defines an 8-step linear sequence to 6-deoxytetracycline antibiotics from three components of similar complexity (cyclohexenone 2, isoxazole ester 3, and structurally diverse D-ring precursors) in which sequential diastereoselective Michael–Claisen cyclization reactions form the A- and C-rings, respectively, of the linearly fused ABCD tetracycline skeleton. In addition to providing a readily scalable, practical route to fully synthetic tetracyclines of broad structural diversity, the sequence reported comprises a series of non-obvious stereoselective transformations, including a novel means for C12a hydroxylation.

[reaction: see text] The first total synthesis of the novel sesquiterpene lactone (+)-8-epi-xanthatin (1) has been achieved starting from the commercially available ester 8. The synthesis features an asymmetric aldol reaction and palladium-catalyzed carbonylation/lactonization sequence leading to 4 and a domino ring-closing enyne metathesis/cross metathesis reaction to afford 1.

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