Application of nitrile oxide cycloadditions to a convergent, asymmetric synthesis of (+)-phyllanthocin

Abstract

A highly convergent, enantioselective total synthesis of (+)-phyllanthocin (l), the aglycon of the novel antineoplastic agent phyllanthoside (2), has been accomplished. The key feature of the approach entailed the dipolar cycloaddition of the nitrile oxide 7 with the optically active, bicyclic lactone 6, a substance that presented a sterically and electronically biased framework to ensure that this reaction proceeded with reasonable levels of regio-and stereoselectivity to afford 11 as the major product. The dispensible oxygen function at C(1) was removed from 11 in three straightforward operations to afford 18, which underwent a directed aldol reaction with the protected aldehyde 8c to give a mixture (1.2:l) of the two adducts 21c and 22c. Treatment of 21c with hydrofluoric acid in methanol gave a mixture of methyl glycosides 23 and 24. Similar treatment of 22c afforded a single methyl glycoside 25, which was transformed into 24 by oxidation and reduction. Unveiling of the latent @-hydroxy ketone array at C(5) and C(7) was achieved by hydrogenolysis and hydrolysis of the isoxazoline ring of 23 and 24 to give intermediates that underwent smooth acid-catalyzed, kinetic spiroketalization to furnish 3 as the major product. The spiroketal3 was then converted into (+)-phyllanthocin (1) according to protocols previously developed by Williams. Brimble, M. A. J. Chem. SOC., Chem. Commun. 1985, 781. (n) Barrett, A. G. M.; Carr, R. A. E.; Attwood, S. V.; Richardson, G.; Walshe, N. D. A.

Enantioselective Halolactonization Reactions using BINOL-Derived Bifunctional Catalysts: Methodology, Diversification, and Applications

“…On the other hand, the utility of 20 as a catalyst to promote kinetic resolutions of racemic olefinic acids is illustrated by the iodolactonizations of 60 and 62 to deliver the corresponding bicyclic iodolactones 61 and 63 in 83:17 er and 78:22 er, respectively (Equations 6 and 7). Both 61 and 63 are important intermediates for the syntheses of several natural products, 17 including sieboldine A 17b and phyllanthocin. 17d …”

“…Both 61 and 63 are important intermediates for the syntheses of several natural products, 17 including sieboldine A 17b and phyllanthocin. 17d …”

Double Cycloadditive Macrocyclization: An Efficient Method for Cyclophane

“…Moreover, isoxazolines are versatile intermediates for the synthesis of bifunctional and naturally occurring compounds and also display important biological activities such as antibacterial , antitubercular , phosphodiesterase inhibitory , anti‐inflammatory , and immunostimulatory , whereas compounds incorporating the pyrazole substructure have stimulated much interest in medicinal and biological chemistries. Meanwhile, functionalized macrocycles are frequently seen in pharmaceutics and natural products , in addition to being important as pharmaceuticals.…”

1,3-Dipolar Cycloaddition in the Synthesis of Novel Isoxazoline/Pyrazole Derivatives Bearing 1,2,3-Triazoles Moiety

“…1,3‐Dipolar cycloaddition has attracted much attention because it is a versatile synthetic strategy for the construction of five‐membered ring heterocycles . The nitrile oxide cycloaddition to alkenes results in the formation of isoxazolines, which are versatile intermediates for the synthesis of bifunctional and naturally occurring compounds and also display important biological activities such as antibacterial , antitubercular, phosphodiesterase inhibitory , antiinflammatory , and immunostimulatory .…”