Diastereoselective multicomponent Amine-Aldehyde-Dienophile (AAD) process for the synthesis of polysubstituted cyclohex-2-enylamines

The multicomponent Amine-Aldehyde-Dienophile reaction is optimized employing benzyl or 4-methoxybenzylamine. The interest of the transformation consist in the synthesis of polysubstituted cyclohex-2-enylamines. The study of the scope of this AAD process is carried out, as well as the diastereoselective version, employing commercially available chiral benzylic amines and a maleimide with the chiral information at the N-substituent. VCD spectroscopy is a very useful tool for the determination of the absolute configuration of the isolated enantiomerically enriched compounds.We gratefully acknowledge financial support from the Spanish Ministerio de Economía y Competitividad (MINECO), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER, EU) (Project Nos. CTQ2013-43446-P, CTQ2014-51912-REDC, CTQ2016-76782-P, CTQ2016-81797-REDC, CTQ2016-81893REDT, and CTQ2016-76155-R), the Generalitat Valenciana (PROMETEOII/2014/017) and the University of Alicante

LiCl-mediated, easy, and low-cost removal of the trityl group from protected alcohols and diols

The reaction of primary, secondary, phenyl, allyl, and benzyl trityl ethers with lithium chloride in methanol at reflux led to deprotection of the trityl group affording the corresponding alcohol in good to excellent yields under mild reaction conditions.This work was financially supported by the Agence National pour le Développement de la Research en Santé (Algérie) and the Spanish Ministerio de Ciencia e Innovación (CTQ2011-24155, CTQ2011-24165), the Ministerio de Economía y Competitividad (CTQ2013-43446-P, CTQ2014-51912-REDC, CTQ2014-53695-P), FEDER, the Generalitat Valenciana (PROMETEO 2009/039, PROMETEOII/2014/017), and the University of Alicante. We also thank the Spanish Ministerio de Asuntos Exteriores y de Cooperación (AP/039112/11)

Dual chiral silver catalyst in the synthetic approach to the core of hepatitis C virus inhibitor GSK 625433 using enantioselective 1,3-dipolar cycloaddition of azomethine ylides and electrophilic alkenes

The asymmetric 1,3-dipolar cycloaddition of an imino ester 5 with tert-butyl acrylate is catalyzed by a dual chiral silver(I) complex formed from a chiral phosphoramidite 14 and the chiral silver(I) binolphosphate (R)-17. This reaction is selected to achieve the synthesis of enantiomerically enriched key structures to access the third generation of GSK HCV inhibitors. The scope of this dual chiral catalytic system is analyzed by employing different imino esters and dipolarophiles, and also compared with the same cycloaddition reactions performed with the chiral phosphoramidite 14·AgClO4 complex.Financial support was provided by the Spanish Ministerio de Ciencia e Innovación (MICINN) (projects CTQ2010-20387, and Consolider Ingenio 2010, CSD2007-00006), the Spanish Ministerio de Economía y Competitividad (MINECO) (projects CTQ2013-43446-P and CTQ2014-51912-REDC), the Spanish Ministerio de Economía, Industria y Competitividad, Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER, EU) (projects CTQ2016-76782-P and CTQ2016-81797-REDC), the Generalitat Valenciana (PROMETEO 2009/039 and PROMETEOII/2014/017), and the University of Alicante

1,3-Dipolar cycloadditions using catalysts with double chirality and novel multicomponent [4+2] processes

In this thesis, different cycloaddition reactions, such as the enantioselective 1,3-dipolar-cycloaddition, which takes place between in situ generated stabilized azomethine ylides, and electrophilic alkenes, and the diastereoselective multicomponent reactions Amine-Aldehyde-Dienophile (AAD) or Phosphoramidate-Aldehyde-Dienophile (PAD) are described. In Chapter 1, an asymmetric 1,3-dipolar cycloaddition reaction involving an imino ester with tert-butyl acrylate was carried out using a silver(I) complex with double chirality, formed from a chiral phosphoramidite and chiral silver binolphosphate(I). The goal of this reaction is to synthesize key enantiomerically enriched structures to access the GSK-third generation of HCV inhibitors. In Chapter 2, the synthesis of polysubstituted cyclohex-2-enylamines using the multicomponent Amine-Aldehyde-Dienophile reaction involving benzyl or 4-methoxybenzylamine, is described. The study the diastereoselective version, employing commercially available chiral benzylic amines, or even a maleimide with the chiral information at the nitrogen atom, are also reported. In Chapter 3, the synthesis of polysubstituted cyclohex-2-enylamines derivatives using the multicomponent Phosphoramidate-Aldehyde-Dienophile (PAD), is described. Several series of N-substituted phosphoramidates reacted with α,β-unsaturated aldehydes, bearing hydrogen atoms at the γ-position, in good yields

Diastereoselective multicomponent phosphoramidate-aldehyde-dienophile (PAD) process for the synthesis of polysubstituted cyclohex-2-enyl-amine derivatives

The reaction of diethyl phosphoramidate, conjugated aldehydes and maleimides takes place in a multicomponent sequence named phosphoramidate-aldehyde-dienophile (PAD). The reaction affords a series of N-substituted phosphoramidates in good yields with α,β-unsaturated aldehydes bearing hydrogens at the γ-position. The reaction is diastereoselective and the effect of chiral information in the maleimide is evaluated. A mechanism is also postulated and the feasible hydrolysis of the phosphoramidate functional group is achieved although the final allylic amine is difficult to isolate.We gratefully acknowledge financial support from the Spanish Ministerio de Economía y Competitividad (MINECO), Agencia Estatal de Investigaci on (AEI) and Fondo Europeo de Desarrollo Regional (FEDER, EU) (Project Nos. CTQ2013-43446-P, CTQ2014-51912-REDC, CTQ2016-76782-P, CTQ2016-81797-REDC, CTQ2016-81893REDT, and CTQ2016-76155-R), the Generalitat Valenciana (PROMETEOII/2014/017) and the University of Alicante

4-Amino-1,2,4-triazoles-3-thiones and 1,3,4-oxadiazoles-2-thiones·palladium(II) recoverable complexes as catalysts in the sustainable Suzuki-Miyaura cross-coupling reaction

The Suzuki-Miyaura cross-coupling reaction using 4-amino-1,2,4-triazoles and 1,3,4-oxadiazoles-2-thiones·palladium (II) is studied. The reaction is optimized and the most appropriate catalytic complex is tested with several aryl halides, boronic acids in an environmentally benign solvent system (H2O/EtOH). The recovery of the catalytic species is also surveyed because of the nature of the employed solvent. A domino process is efficiently carried out following the standard conditions. Several surface parameters of the ligands are analyzed and the resulting values are extrapolated to the insoluble palladium catalyst.We gratefully acknowledge financial support from the Spanish Ministerio de Ciencia, Innovación y Universidades (projects CTQ2016-76782-P, CTQ2016-81797-REDC CTQ2016-81893REDT, and RED2018-102387-T) the Spanish Ministerio de Economía, Industria y Competitividad, Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER, EU) (projects CTQ2016-76782-P), the Generalitat Valenciana (PROMETEOII/2014/017), USTO-MB and the Universities of Mersin and Alicante. One of us (M.C.) thanks USTO-MB for scientific leave