Reversal of Diastereoselection in the Conjugate Addition of Cuprates to Unsaturated Lactams

Abstract

We report that the stereochemical outcome of the conjugate addition of organocopper reagents to bicyclic α,β-unsaturated lactams derived from pyroglutaminol is determined by the nature of the aminal group. Bicyclic α,β-unsaturated lactams in which the aminal is derived from a ketone have been found to afford products of syn conjugate addition. By contrast, bicyclic α,β-unsaturated lactams in which the aminal is derived from an aldehyde afford products of anti conjugate addition. These remarkably different results obtained from very similar starting materials are unexpected.

Synthetic Exploration of α‐Diazo γ‐Butyrolactams

“…Alternatively, this transformation may proceed via protonation of the α‐diazocarbonyl moiety followed by elimination of a nitrogen molecule. 3‐Pyrrolin‐2‐ones are versatile substrates for addition of organometallic compounds, Michael addition and 1,3‐dipolar cycloaddition . At the same time, the principal methods employed in their preparation are olefin metathesis and oxidative elimination of α‐phenylselenyl lactams , .…”

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

“…The stereocontrol is often unremarkable; however, compared with the more popular benzylidene analog 1a , the acetonide-protected variant 1b enhances the preference for functionalization from the convex face. 1,8,15 Given the potential importance of these synthons, surprisingly few variants of the hemiaminal linkage have been reported. 1 …”

“…1,8,15 Given the potential importance of these synthons, surprisingly few variants of the hemiaminal linkage have been reported. 1 …”

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

“…Our collaborators in the Pfizer group are motivated by medicinal chemistry interests: the bicyclo[3.3.0] ring system is a potential source of stereocontrol needed for a program to develop anti-inflammatory agents. 1 The interest of the Collum group was piqued by the flexibility offered by the hemiaminal linkage that might be used to modify enolate structure, reactivity, and reaction mechanism. Our interest in imine chemistry in general 8 and the azaaldol addition in particular 7 stems from the versatility of the two imine appendages in modulations of structure–reactivity relationships.…”