Lithium Enolates Derived from Pyroglutaminol: Aggregation, Solvation, and Atropisomerism

Abstract

Lithium enolates derived from protected pyroglutaminols were characterized by using 6Li, 13C, and 19F NMR spectroscopies in conjunction with the method of continuous variation. A mixture of tetrasolvated dimers and tetrasolvated tetramers in proportions depend on the steric demands of the hemiaminal protecting group, tetrahydrofuran concentration, and the presence or absence of an α-fluoro moiety. The high steric demands of the substituted bicyclo[3.3.0] ring system promote dimers to an unusual extent and allow solvents and atropisomers in cubic tetramers to be observed in the slow-exchange limit. Pyridine used as a 6Li chemical shift reagent proved useful in assigning solvation numbers.

Lithium Enolates Derived from Pyroglutaminol: Mechanism and Stereoselectivity of an Azaaldol Addition

“…Organolithium chemists may be tempted to invoke addition via previously characterized LDA–enolate mixed dimer 5 . 3 Once again, this would be wrong. An analogous endo selectivity was detected by Moloney and coworkers 9 and suggested to arise from an intervening dianion.…”

“…Similarly, mixed aggregate 5 was previously characterized with 6 Li and 15 N NMR spectroscopies 10 using [ 6 Li, 15 N]LDA 11 and augmented by computational studies. 3 The same methods were used to characterize an intermediate dianion ( vide infra ). Structural and mechanistic studies were supported by density functional theory (DFT) calculations at the B3LYP/6–31G(d) level with single-point calculations at the MP2 level of theory.…”

“…2 Acetonide-protected derivative 1a shows more promise than the more popular benzylidene analog 1b . 3 Rarely reported functionalization from the concave face relies largely on epimerization and is poorly selective. 4 …”

“… The readily available hemiaminals of pyroglutaminol have been subjects of intense scrutiny and can be functionalized exofacially with moderate selectivity sufficient for many applications . Acetonide-protected derivative 1a shows more promise than the more popular benzylidene analog 1b . Rarely reported functionalization from the concave face relies largely on epimerization and is poorly selective …”

“…The Collum group became interested in lithium enolates in hopes of correlating their structure and solvation with the stereochemistry of their functionalizations . We have previously described structural studies of a dozen enolates within the class, all of which form mixtures of tetrasolvated tetramers and tetrasolvated dimers as exemplified by acetonide-derived enolates (Chart ). These enolates are deceptively hindered, causing observable atropisomerism and slow solvent exchanges within the tetramer form.…”