Proline Catalyzed α-Aminoxylation Reaction in the Synthesis of Biologically Active Compounds

Abstract

The search for new and efficient ways to synthesize optically pure compounds is an active area of research in organic synthesis. Asymmetric catalysis provides a practical, cost-effective, and efficient method to create a variety of complex natural products containing multiple stereocenters. In recent years, chemists have become more interested in using small organic molecules to catalyze organic reactions. As a result, organocatalysis has emerged both as a promising strategy and as an alternative to catalysis with expensive proteins or toxic metals. One of the most successful and widely studied secondary amine-based organocatalysts is proline. This small molecule can catalyze numerous reactions such as the aldol, Mannich, Michael addition, Robinson annulation, Diels-Alder, α-functionalization, α-amination, and α-aminoxylation reactions. Catalytic and enantioselective α-oxygenation of carbonyl compounds is an important reaction to access a variety of useful building blocks for bioactive molecules. Proline catalyzed α-aminoxylation using nitrosobenzene as oxygen source, followed by in situ reduction, gives enantiomerically pure 1,2-diol. This molecule can then undergo a variety of organic reactions. In addition, proline organocatalysis provides access to an assortment of biologically active natural products including mevinoline (a cholesterol lowering drug), tetrahydrolipstatin (an antiobesity drug), R(+)-α-lipoic acid, and bovidic acid. In this Account, we present an iterative organocatalytic approach to synthesize both syn- and anti-1,3-polyols, both enantio- and stereoselectively. This method is primarily based on proline-catalyzed sequential α-aminoxylation and Horner-Wadsworth-Emmons (HWE) olefination of aldehyde to give a γ-hydroxy ester. In addition, we briefly illustrate the broad application of our recently developed strategy for 1,3-polyols, which serve as valuable, enantiopure building blocks for polyketides and other structurally diverse and complex natural products. Other research groups have also applied similar strategies to prepare such bioactive molecules as littoralisone, brasoside and (+)-cytotrienin A. Among the various synthetic approaches reported for 1,3-polyols, our organocatalytic iterative approach appears to be very promising and robust. This method combines the merit of organocatalytic reaction with an easy access to both enantiomerically pure forms of proline, mild reaction conditions, and tolerance to both air and moisture. In this Account, we present the latest applications of organocatalysis and how organic chemists can use this new tool for the total synthesis of complex natural products.

Total Synthesis and Biological Assessment of Mandelalide A

“…The 23 R configuration of ent ‐ 25 (and thus ent ‐ 5 ; mandelalide numbering) was assigned on the basis of the established stereochemical course of proline‐catalyzed oxyamination reactions; the oxyamination product was identical with the major product obtained from the dihydroxylation of ent ‐ 24 with either AD‐mix‐β or ‐α. At the same time, ent ‐ 25 , apart from the sign of its optical rotation, was identical with the major diol produced by dihydroxylation of 24 with AD‐mix‐α or ‐β (Scheme ), thus confirming the 23 S configuration of diol 25 .…”

Organocatalysts Derived from Unnatural α‐Amino Acids: Scope and Applications

“…There are several examples of organocatalytic synthesis of biologically active compounds, although most of them rely on organocatalysts derived from prolinol or cinchona alkaloids. [100] The synthesis of novel or known drugs at the gram or kilogram scale by using organocatalysts derived from unnatural amino acids will reflectt he maturity of the field. It is expected that novel noncovalent synthetic organocatalysts based on densely substituted a-aminoa cid scaffolds will result in lower catalyst loadings, wider scope, highers cale, and even novel stereocontrolled processes not accessible to already known organocatalysts based on natural a-amino acids, phosphoric acids, ureas, squaramides, phosphines, carbenes,o rc inchona alkaloids.…”

Indolo[2,3-a]quinolizidines and Derivatives: Bioactivity and Asymmetric Synthesis

“…However, although this area is under intense study, there are still few reports [88,89] on the application of this methodology for asymmetric total synthesis of natural products. Scheme 23  Enantioselective total synthesis of (+)-arborescidine A (13).…”