Crystallization-Enabled Henry Reactions: Stereoconvergent Construction of Fully Substituted [N]-Asymmetric Centers

Abstract

Tetrasubstituted stereogenic carbon centers bearing a nitrogen substituent represent important motifs in medicinal chemistry and natural products; therefore, the development of efficient methods for the stereoselective synthesis of this class of compounds continues to be an important problem. This article describes stereoconvergent Henry reactions of γ,γ-disubstituted nitroalkanes to deliver highly functionalized building blocks containing up to five contiguous stereogenic centers including a fully substituted [N]-asymmetric center. Henry reactions of higher order nitroalkanes are often characterized by their reversibility and minimal accompanying thermodynamic stereocontrol. In contrast, mechanistic studies for the present case suggest a scenario in which reversibility is productively leveraged through crystallizationbased stereocontrol, thereby enabling the efficient sequential π-additions of readily accessible starting materials to assemble complex acyclic stereoarrays.

Multistep Cascade Catalytic Reactions Employing Bifunctional Framework Compounds

“…To check the reactivity of the Lewis base-catalyzed reaction, we attempted the Henry reaction . The Henry reaction is the reaction between nitroalkane and an aldehyde or ketone catalyzed by a base to form β-nitro alcohol. − To this end, equimolar quantities of nitromethane and benzaldehyde (1 mmol) were reacted in an RB flask with 5 mL of H 2 O in the presence of 1.6 mol % of catalyst (compound I ) at 100 °C. This reaction produced two products, 2-nitro-1-phenylethanol (C) and trans -β-nitrostyrene (D) with yields of ∼46 and ∼11%, respectively, in 2 h of the reaction.…”

Conglomerate Crystallization in the Cambridge Structural Database (2020–2021)

“…Exploiting crystallization as a means to achieve asymmetric synthesis is not typically considered by synthetic chemists. Recent reports of crystallization-driven enantioselective syntheses have demonstrated impressive stereocontrol in their products. , Protocols which combine a cocrystallization event with solution phase racemization also demonstrate the viability of combining synthetic transformations with crystallization in producing enantioenriched materials. − While these protocols are not classed as spontaneous deracemizations, since they employ an enantioenriched agent to bias the diastereomeric relationship in the crystal, they highlight the possibility of engineering a conglomerate via cocrystallization and racemizing the desired stereocenter(s) in order to achieve a spontaneous deracemization. Excitingly, a recent report of cocrystallization of two racemic compounds to form a stable conglomerate system allowed for the preferential crystallization and resolution of both compounds .…”

Conglomerate Crystallization in the CSD (2020–2021)

“…Recent reports of crystallization-driven enantioselective syntheses have demonstrated impressive stereocontrol in their products. 28,29 Protocols which combine a co-crystallization event with solution phase racemization also demonstrate the viability of combining synthetic transformations with crystallization in producing enantioenriched materials. [30][31][32] Whilst these protocols are not classed as spontaneous deracemizations, since they employ an enantioenriched agent to bias the diastereomeric relationship in the crystal, they highlight the possibility of engineering a conglomerate via co-crystallization and racemizing the desired stereocenter(s) in order to achieve a spontaneous deracemization.…”