Transition Metal/Base-Catalyzed Aldol Reactions of Isocyanoacetic Acid Derivatives with Prochiral Ketones, a Straightforward Approach to Stereochemically Defined β,β-Disubstituted-β-hydroxy-α-amino Acids.¹ Scope and Limitations

Abstract

A systematic study of the transition metal/base-catalyzed aldol reactions of methyl isocyanoacetate with a wide range of prochiral ketones, giving rise to the 4-(methoxycarbonyl)-5,5-disubstituted-2-oxazolines, has been made. The diastereoselectivity of these reactions was found to be influenced by a mix of several factors, including steric characteristic of the substituents, nature of the catalyst, electrostatic, and electron donor−acceptor type interactions. The former factor, a stereochemical discrimination between the substituents at the ketone carbon, was shown to be the most pronounced in controlling of the stereochemical outcome, which could be markedly improved with a proper choice of the catalyst. In particular, for the reactions of methyl isocyanoacetate with polyhaloalkyl aryl(alkyl) ketones, high diastereoselectivity (80−98% de) was achieved, thus allowing for straightforward and generalized access to the corresponding (2R*,3R*)-β,β-disubstituted-β-hydroxy-α-amino carboxylic acid.

Self-disproportionation of enantiomers of thalidomide and its fluorinated analogue via gravity-driven achiral chromatography: mechanistic rationale and implications

“…Although the reason for the fluorine effect on the conformational change is not clear, it could be explained by the electrostatic repulsion between the fluorine and the two carbonyls of the piperidine-2,6-dione ring, and/or a strong dipole induced by the fluorine atom. 14 Namely, the equatorial-fluorine conformation of 2 is presumably preferable, since the fluorine exists on the same plane as the two carbonyls of piperidine-2,6-dione in 2 . On the other hand, the fluorine is almost perpendicular to the two carbonyls in the axial-fluorine conformation of 2 , resulting in less-stabilization.…”

Internal chirality descriptors iR and iS and ire and isi. A proposed notation to extend the usefulness of the R/S system by retaining the sense of stereochemistry in cases of ligand ranking changes

“…The same conundrum to unambiguously convey the sense of the stereochemical course of the reaction and/or the sense of the stereochemistry of the products as in Brown's work was encountered in the (chiral) metal complex‐catalyzed diastereomeric (and asymmetric) aldol reactions of alkyl aryl (alkyl) ketones 23 . In these works, the substrates were varied while the nucleophile (methyl isocyanoacetate) was invariant.…”

Boron-Catalyzed Carboxylic Acid-Selective Aldol Reaction with Trifluoromethyl Ketones

“…[16][17][18][19][20][21][22][23][24][25] In contrast, the use of nucleophiles with a carboxylic acid oxidation state is scarcely developed, even for racemic aldol reactions with trifluoromethyl ketones. Moreover, almost all preceding studies relied on active methylene compounds (Chart 1a), such as isocyanoacetic acid derivatives, 26,27) ethyl diazoacetate, 28) and malonic acid half esters, 29) or pre-activated ketene silyl acetals (Chart 1b). [30][31][32] Because of the high pK a values of the α-proton of simple carboxylic acid derivatives, a direct catalytic aldol reaction of non-activated carboxylic acid derivatives remained to be explored.…”