Chemo- and stereoselective reduction of enaminones for the preparation of biologically active compounds

Abstract

The chemistry of the preparation of β-enamino ketones and β-enamino esters and their use as useful starting materials in reductive procedures for the preparation of biologically active natural products is described.Enaminones are very stable compounds and can be easily prepared, starting from cheap and easily available starting materials. Therefore they constitute also excellent starting materials in organic synthesis. Several chemo-and regioselective methodologies for their preparation have been developed also recently. The possibility to use enantiopure chiral amines for the preparation of enamino ketones and enamino esters makes available useful starting materials for the preparation of enantiopure biologically active compounds. Moreover, it is possible to obtain more complex enaminones by regio-and stereoselective functionalization of the more accessible ones.Recently numerous methodologies for the chemo-and stereoselective reduction of enaminones have been developed, that constitute useful alternative pathways to the numerous literature procedures for the preparation of γ-amino alcohols, β-amino acids, aminoalkyl phenols and their derivatives. γ-Aminoalcohols and aminoalkylphenols are a class of very stable compounds that find useful applications in asymmetric catalysis as chelant for the preparation of chiral enantiopure metallic catalysts.

Practical, Asymmetric Route to Sitagliptin and Derivatives: Development and Origin of Diastereoselectivity

“…Intermediate 4 was synthesized by combining ketoamide 3 and ( R )-(+)-phenylethylamine in toluene with 1.6 equiv of acetic acid at 110 °C . In this experiment, only the Z -isomer was observed in the quantitative conversion to 4 due to the highly stabilizing hydrogen bond described above (see also below) …”

“…Inspection of the key proposed substrate 4 reveals an α,β-unsaturated amide which permits a very different approach relative to metal-catalyzed hydrogenation. It was envisioned that the carbonyl group of the enone would engage in hydrogen bonding with the amino group of the auxiliary giving rise to conformationally well-defined system 4 where the amino group is predominantly sp 2 . Consequently, allylic strain would cause the auxiliary to impose a facial bias during external delivery of hydride to the β-site.…”

“…Having achieved an expedient synthesis of 4 , the next task was to devise a suitable reagent system for reduction. In this context, several borohydride species precedented in the this reduction [NaBH 4 , NaB­(OAc) 3 H, and NaBH 3 CN] were studied but resulted in no conversion with the β-enamino amide being recovered (Scheme ). Undeterred, we hypothesized that a Lewis acidic reductant would allow internal hydride delivery, which is not possible with the aforementioned reductants.…”

Efficient PPA-SiO2-catalyzed Synthesis of β-enaminones Under Solvent-Free Conditions

“…Enaminones are important building blocks in organic synthesis which can be further transformed into valuable bioactive nitrogen heterocylces [4,5,6], natural therapeutic agents and alkaloids [5,6]. They are also used as precursors for the synthesis of various types of compounds like N-substituted carbazolones [7], peptides [8], quinolines [9,10], azocompounds [11,12], α,β-aminoacids [13,14] that serve important roles in asymmetric catalysis via chelating agents [15]. Enaminones are known to affect several physiological functions themselves or are precursors for such molecules, in particular as anticonvulsant [16], anti-epileptic [17], anti-inflammatory [18] and antitumor agents [19,20,21].…”

Phosphotungstic Acid Catalysed Synthesis of β-Enamino Compounds under Solvent-Free Conditions

“…25 b-Enamino compounds have been extensively used as intermediates in organic synthesis. [26][27][28][29] In particular, they have been utilised as synthons for the synthesis of various biologically active heterocyclic compounds having antiinflammatory, antitumor, antibacterial, and anticonvulsant activities [30][31] and as intermediates for the preparation of b-enaminoacids, g-enaminoaclohols, and b-enamino esters. 32 Due to its wide range of utility in the pharmaceutical industry, the enamination of β-dicarbonyl compounds with various amines has become an important transformation and consequently several methods have been developed for the synthesis of these compounds.…”