Stereocontrolled Alkylative Construction of Quaternary Carbon Centers

Abstract

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...

Acceleration of the Substitution of Silanes with Grignard Reagents by Using either LiCl or YCl3/MeLi

“…The resulting heterogeneous mixture was filtered through Celite, which was rinsed with diethyl ether. The organic phase was dried over Na 2 SO 4 and concentrated in vacuo to give a crude oil, which was chromatographed on silica gel (eluent: hexanes) to afford the title compound (139 mg, 86 %) as a colorless oil. The product was fully characterized by .…”

“…[3] Herein we show that the practical substitution of silanes with Grignard reagents is possible in the presence of LiCl [4] as formulated in Equation (1). [5] The impressive effect of the lithium salt upon the substitution of a silane is highlighted below.…”

“…For example, the benzyltitanium reagent 7, prepared in situ from equimolar amounts of PhCH 2 MgCl and Ti(OiPr) 4 , [9] is almost inert to PhSiH 3 , but the addition of LiCl to this mixture promoted the reaction to give 8 in a better yield [Eq. (10)].…”

Stereodefined acyclic trisubstituted metal enolates towards the asymmetric formation of quaternary carbon stereocentres

“…Thus, pseudoephedrine-based a-branched amides selectively formed Z-and E-enolates upon deprotonation, as confirmed from the nOe spectra of the corresponding cyclic siloxane derivatives (Scheme 4). 34 The rationalization for the favored pre-transition state suggested that the solvated lithium alkoxide side chain and the base are positioned on opposite faces of the forming enolate, with the R-C-H bond suitably aligned for deprotonation ( Fig. 2).…”

Design and Synthesis of 2-Nitroimidazoles with Variable Alkylating and Acylating Functionality

“…The condensing agents used for Methods B and C complement other reagents (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, diisopropylcarbodiimide) that are frequently used to acylate β-amino alcohols with acrylic acids. 14,15) All precursor anhydrides and acids were commercially available except for (S)-4-oxo-2-azetidinecarboxylic acid, which was synthesized by the procedure of Baldwin et al 16) We also aminated epoxide 3 with allylamine to give 6 in 67% yield. We view the terminal olefin as a convenient functional group to introduce electrophilic functionality onto the amine side chain toward making homologous analogs of 1a.…”