Mixed Aggregates of the Dilithiated Koga Tetraamine: NMR Spectroscopic and Computational Studies

Abstract

A combination of 1 H, 6 Li, 13 C, and 15 N NMR spectroscopies and density functional theory computations explores the formation of mixed aggregates by a dilithium salt of a C 2 -symmetric chiral tetraamine (Koga's base). Lithium halides, acetylides, alkoxides, and monoalkylamides form isostructural trilithiated mixed aggregates with few exceptions. 6 Li-13 C and 6 Li-15 N couplings reveal heretofore undetected transannular contacts (laddering) with lithium acetylides and lithium monoalkylamides. Marked temperature-dependent 15 N chemical shifts seem to be affiliated with this laddering. Computational studies shed light on the general structures, penchant for laddering, and stereochemical consequences of aggregation. Graphical AbstractKoga's chiral dilithium amide used in asymmetric synthesis is shown to promiscuously form mixed aggregates with a wide variety of lithium salts including those containing halides, alkoxides, acetylides, and amides. Although largely isostructural, the presence or absence of Li-X transannular contacts distinguishes ladder from cyclic motifs. KeywordsLithium; NMR Spectroscopy; Aggregation; Synthetic Methods; Enantioselectivity C 2 -symmetric dilithiated tetraamine 1, developed by Koga and coworkers [1] as a chiral Brønsted base, has proven to be a versatile, non-covalent auxiliary for enantioselective synthesis. [2,3] Amgen [2] effected asymmetric alkylations of simple enolates en route to Correspondence to: David B. Collum; Armen Zakarian. Supporting information for this article is given via a link at the end of the document. (1)], and one of us (AZ) [3] developed enantioselective asymmetric alkylations and 1,4-additions of enediolates (Scheme 1). [4] The exceptional selectivities prompted a collaboration to study the structures of putative mixed aggregates derived from dilithiated enediolates and dianion 1. [5] Despite the potential complexities of characterizing mixtures of two dianions, mixed aggregates 2 (containing n-BuLi) and 3 (containing dilithium enediolate) proved structurally tractable and yielded a computationally viable and predictive stereochemical model. [5] (1) HHS Public AccessInstances in which highly stereoselective organolithium reactions have been traced to specific solvation and aggregation effects, [6] control of aggregate structure appears to accompany-and possibly be a prerequisite for-high stereocontrol. With that hypothesis in mind, we surveyed the structures of mixed aggregates of 1 with a variety of lithium salts (Chart 1). Dianion 1 is a promiscuous pairing partner, affording isostructural mixed aggregates 4 or the corresponding ladder structures 5 (distinguished by a transannular Li-X contact). [7] Spectroscopic and computational studies revealed structural nuances, including the stereochemical consequences of aggregation. [8][9][10] Mixed aggregation of 1 was examined with 6 Li NMR spectroscopy. We routinely used minor excesses of n-BuLi-derived mixed aggregate 2 to generate the new mixed aggregates from LiX precursors, which caused low conce...