Multicomponent synthesis of unnatural pyrrolizidines using 1,3-dipolar cycloaddition of proline esters

The synthesis of unnatural pyrrolizidines has been studied using a multicomponent-domino process involving proline or 4-hydroxyproline esters, an aldehyde and a dipolarophile. The formation of the iminium salt promotes the 1,3-dipolar cycloaddition affording highly substituted pyrrolizidines under mild conditions and high regio- and diastereoselectivities.This work has been supported by the DGES of the Spanish Ministerio de Ciencia e Innovación (MICINN) (Consolider INGENIO 2010 CSD2007-00006, CTQ2007-62771/BQU, CTQ2010-20387), FEDER Generalitat Valenciana (PROMETEO/2009/039), and by the University of Alicante

Binap-silver salts as chiral-catalysts for the enantioselective 1,3-dipolar cycloaddition of azomethine ylides and alkenes

Binap-AgSbF6 catalyzed 1,3-dipolar cycloadditions between azomethine ylides and electrophilic alkenes are described and compared with analogous transformations mediated by other Binap-silver(I) salt complexes. Maleimides and 1,2-bis(phenylsulfonyl)ethylene are suitable dipolarophiles for obtaining very good enantioselectivities, even better values are generated by a multicomponent version. There are some very interesting applications of the disulfonylated cycloadducts in the total synthesis of cis-2,5-disubstituted pyrrolidines, precursors of natural products, or valuable intermediates in the synthesis of antiviral compounds.This work has been supported by the Spanish Ministerio de Ciencia e Innovación (MICINN) through the Hispano-Brazilian project PHB2008-0037-PC and CNPq-2878, Consolider INGENIO 2010 CSD2007-00006, CTQ2010-20387, FEDER, Generalitat Valenciana (PROMETEO/2009/039), and by the University of Alicante. MM-R thanks MEC for a predoctoral fellowship. EC thanks CNPq for a predoctoral Doutorado Sanduíche stay

Enantioselective synthesis of polysubstituted prolines by Binap-silver-catalyzed 1,3-dipolar cycloadditions

The enantioselective 1,3-dipolar cycloaddition reaction of stabilized azomethine ylides, generated from iminoesters, with maleimides was efficiently achieved by intermediacy of an equimolar mixture of chiral (R)- or (S)-Binap and AgClO4. The high stability of the titled catalytic metal-complex to light exposure and its insolubility in toluene made possible its recovery and reutilization in other new process. In order to get a better understanding of the behavior of these chiral catalysts, we have carried out DFT1 calculations demonstrating the experimentally observed high enantio- and endo-selectivity through a very asynchronous transition state.This work has been supported by the DGES of the Spanish Ministerio de Educación y Ciencia (MEC) (Consolider INGENIO 2010 CSD2007-00006, CTQ2007-62771/BQU, and CTQ2004-00808/BQU), Generalitat Valenciana (CTIOIB/2002/320, GRUPOS03/134 and GV05/144), and by the University of Alicante. M.G. Retamosa thanks the University of Alicante for a predoctoral fellowship

Binap-gold(I) trifluoroacetate as a bifunctional catalyst for the synthesis of chiral prolines through 1,3-dipolar cycloaddition of azomethine ylides

Highly enantioselective 1,3-dipolar cycloadditions of amino acid-derived azomethine ylides with alkenes have been performed, for the first time, under gold-catalysis using (Sa)- or (Ra)-Binap-gold(I) trifluoroacetate complexes, with the cationic Binap-gold acting as a Lewis acid and the counteranion as a base. Maleimides and trans-1,2-bis(phenylsulfonyl)ethylene were reacted with imino esters at room temperature in the absence of a base to afford, in very good yields, the corresponding polysubstituted prolines with total endo-diastereoselection and higher enantioselectivities than the Binap-silver trifluoroacetate complex.This work has been supported by the DGES of the Spanish Ministerio de Educación y Ciencia (MEC) (Consolider INGENIO 2010 CSD2007-00006, and CTQ2007-62771/BQU), by the Generalitat Valenciana (PROMETEO/2009/039), and by the University of Alicante. M.M.-R. thanks MEC for a predoctoral fellowship and F.-L. W. thanks the UQ Graduate School for a Research Travel Grant

Enantioselective synthesis of proline derivatives by 1,3-dipolar cycloadditions

Research devoted to the synthesis of highly substituted prolines, which are hepatitis C virus inhibitors, using 1,3-dipolar cycloadditions (1,3-DC) of azomethine ylides is described. In the first part, a diastereoselective approach using an inexpensive lactate-derived acrylate as dipolarophile is described. In the second part, our efforts using simple and easily accessible chiral silver(I) and gold(I) complexes as catalysts for enantioselective synthesis of proline derivatives are reviewed. In this case, chiral phosphoramidites and binap have been used as privileged ligands. Parallel to these experimental results, considerable effort was dedicated to run semiempirical density functional theory (DFT) calculations to explain and justify the stereoselectivity of each process.This work has been supported by the DGES of the Spanish Ministerio de Ciencia e Innovación (MICINN) (Consolider INGENIO 2010 CSD2007-00006, FEDER-CTQ2007-62771/BQU, and by the Hispano-Brazilian project PHB2008-0037-PC), Generalitat Valenciana (PROMETEO/2009/039), and by the University of Alicante (GITE-09020-UA)

1,3-Dipolar cycloadditions: applications to the synthesis of antiviral agents

In the present perspective the advances and real possibilities of 1,3-dipolar cycloadditions as key steps in the total synthesis of virus inhibitors are described. Azides, nitrones, and azomethine ylides are the most appropriate 1,3-dipoles for the synthesis of privileged structures with the highest biological responses against viruses.This work has been supported by the DGES of the Spanish Ministerio de Educación y Ciencia (MEC) (Consolider INGENIO 2010 CSD2007-00006, CTQ2007-62771/BQU, and CTQ2004-00808/BQU), and by the University of Alicante