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

Abstract

A lithium enolate derived from an acetonide-protected pyroglutaminol undergoes a highly selective azaaldol addition with (E)–N–phenyl–1–[2–(trifluoromethyl)phenyl]methanimine. The selectivity is sensitive to THF concentration, temperature, and the presence of excess lithium diisopropylamide base. Rate studies show that the observable tetrasolvated dimeric enolate undergoes reversible deaggregation, with the reaction proceeding via a disolvated-monomer-based transition structure. Limited stereochemical erosion stems from the intervention of a trisolvated-monomer-based pathway, which is suppressed at low THF concentrations and elevated temperature. Endofacial selectivity observed with excess lithium diisopropylamide (LDA) is traced to an intermediate dianion formed by subsequent lithiation of the monomeric azaaldol adduct, which is characterized as both a dilithio form and a trilithio dianion–LDA mixed aggregate.

Lithium Diisopropylamide: Nonequilibrium Kinetics and Lessons Learned about Rate Limitation

“…The relative rate law assumes special importance for documenting the origins of minor impurities or selectivities when the influence of the minor pathway on the rates cannot be measured directly. 8d,25 …”

“…For example, the relative proportions of two products might be independent of LDA concentration and linearly dependent on THF concentration, which shows that the two product-determining transition structures differ by a single THF ligand. The relative rate law assumes special importance for documenting the origins of minor impurities or selectivities when the influence of the minor pathway on the rates cannot be measured directly. , …”

Mimics of pramanicin derived from pyroglutamic acid and their antibacterial activity

“…Although it has been noted that the bicyclic system generally exhibits exostereoselectivity in its reactions on the less hindered convex face as seen in this case and as might be expected, 39 it is nonetheless possible to favour endo-selectivity in the alkylations of the lactam enolates by use of acetophenone protected systems. 40,41 Overall, conversion of (7S)-6 is best with alkynyl Grignard reagents, followed by aryl and alkyl Grignard reagents, with the bulky isobutyl Grignard reagent giving the lowest conversion, suggesting that the steric requirements in the vicinity of the endo-Weinreb amide dictate the course of the reaction, as might be expected. In order to probe this behaviour further, a competition reaction of 6 using phenylethnyl magnesium bromide and isobutyl magnesium bromide added simultaneously was conducted.…”

“…(apparent dq, J = 6.7, 8.7 Hz, 1H, H-5), 3.62 (t, J = 8.4 Hz, 1H, H-4'), 2.96 (dd, J = 7.0, 13.9 Hz, 1H, H-6), 2.38 (t, J = 7.1 Hz, 2H, H-12), 2.10 (dd, J = 6.6, 14.0 Hz, 1H, H-6'), 1 41. 1.50 (m, 2H, H-13), 1.26-1.39 (m, 2H, H-14), 0.85 (t, J = 7.3 Hz, 3H, H-15); δ C (100 MHz, MeCN-d 3 ) 185.08…”