Pyrimidine‐Derived Prolinamides as Recoverable Bifunctional Organocatalysts for Enantioselective Inter‐ and Intramolecular Aldol Reactions under Solvent‐Free Conditions

Chiral L-prolinamides 2 containing the (R,R)- and (S,S)-trans-cyclohexane-1,2-diamine scaffold and a 2-pyrimidinyl unit are synthesized and used as general organocatalysts for intermolecular and intramolecular aldol reactions with 1,6-hexanedioic acid as a co-catalyst under solvent-free conditions. The intermolecular reaction between ketone–aldehyde and aldehyde–aldehyde must be performed under wet conditions with catalyst (S,S)-2b at 10 °C, which affords anti-aldols with high regio-, diastereo-, and enantioselectivities. For the Hajos–Parrish–Eder–Sauer–Wiechert reaction, both diastereomers of catalyst 2 give similar results at room temperature in the absence of water to give the corresponding Wieland–Miescher ketone and derivatives. Both types of reactions were scaled up to 1 g, and the organocatalysts were recovered by extractive workup and reused without any appreciable loss in activity. DFT calculations support the stereochemical results of the intermolecular process and the bifunctional role played by the organocatalyst by providing a computational comparison of the H-bonding networks occurring with catalysts 2a and 2b.

[1]  G. Guillena,et al.  Enantioselective aldol reactions with aqueous 2,2-dimethoxyacetaldehyde organocatalyzed by binam-prolinamides under solvent-free conditions , 2014 .

[2]  G. Guillena,et al.  Solvent-Free Enantioselective Organocatalyzed Aldol Reactions , 2014 .

[3]  G. Guillena,et al.  Aqueous organocatalyzed aldol reaction of glyoxylic acid for the enantioselective synthesis of α-hydroxy-γ-keto acids , 2014 .

[4]  J. Młynarski,et al.  Catalytic asymmetric aldol reactions in aqueous media--a 5 year update. , 2014, Chemical Society reviews.

[5]  K. Jørgensen,et al.  Hydrogen-bonding in aminocatalysis: from proline and beyond. , 2014, Chemistry.

[6]  R. Sebastián,et al.  Recoverable silica-gel supported binam-prolinamides as organocatalysts for the enantioselective solvent-free intra- and intermolecular aldol reaction , 2013 .

[7]  M. Heravi,et al.  Recent applications of organocatalysts in asymmetric aldol reactions , 2012 .

[8]  G. Guillena,et al.  Cross‐Linked‐Polymer‐Supported N‐{2′‐[(Arylsulfonyl)amino][1,1′‐binaphthalen]‐2‐yl}prolinamide as Organocatalyst for the Direct Aldol Intermolecular Reaction under Solvent‐Free Conditions , 2012 .

[9]  Liang Huang,et al.  Organosilane micellization for direct encapsulation of hydrophobic quantum dots into silica beads with highly preserved fluorescence. , 2012, Chemical communications.

[10]  E. Juaristi,et al.  Recent efforts directed to the development of more sustainable asymmetric organocatalysis. , 2012, Chemical communications.

[11]  Ben Bradshaw,et al.  The Wieland-MiescherKetone: A Journey from Organocatalysis to Natural Product Synthesis , 2012 .

[12]  S. K. Panday Advances in the chemistry of proline and its derivatives: an excellent amino acid with versatile applications in asymmetric synthesis , 2011 .

[13]  G. Guillena,et al.  Solvent-free direct enantioselective aldol reaction using polystyrene-supported N-sulfonyl-(Ra)-binam-D-prolinamide as a catalyst , 2010 .

[14]  L. Gong,et al.  The role of double hydrogen bonds in asymmetric direct aldol reactions catalyzed by amino amide derivatives. , 2010, Chemical communications.

[15]  B. Trost,et al.  The direct catalytic asymmetric aldol reaction. , 2010, Chemical Society reviews.

[16]  J. Bonjoch,et al.  Total synthesis of (-)-anominine. , 2010, Journal of the American Chemical Society.

[17]  Lili Lin,et al.  Amide-based bifunctional organocatalysts in asymmetric reactions. , 2009, Chemical communications.

[18]  J. Bonjoch,et al.  Efficient Solvent-Free Robinson Annulation Protocols for the Highly Enantioselective Synthesis of the Wieland–Miescher Ketone and Analogues , 2009 .

[19]  G. Guillena,et al.  N-Tosyl-(Sa)-binam-L-prolinamide as highly efficient bifunctional organocatalyst for the general enantioselective solvent-free aldol reaction , 2008 .

[20]  D. Truhlar,et al.  The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals , 2008 .

[21]  H. Ha,et al.  Selective Mono‐BOC Protection of Diamines , 2007 .

[22]  Tsubasa Okano,et al.  Dry and wet prolines for asymmetric organic solvent-free aldehyde-aldehyde and aldehyde-ketone aldol reactions. , 2007, Chemical communications.

[23]  F. Jiang,et al.  Protonated N'-benzyl-N'-prolyl proline hydrazide as highly enantioselective catalyst for direct asymmetric aldol reaction. , 2006, Chemical communications.

[24]  Lin-feng Cun,et al.  A Highly Efficient Organocatalyst for Direct Aldol Reactions of Ketones with Aldedydes , 2005 .

[25]  F. Jiang,et al.  Enantioselective direct aldol reactions catalyzed by L-prolinamide derivatives. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[26]  F. Jiang,et al.  Novel small organic molecules for a highly enantioselective direct aldol reaction. , 2003, Journal of the American Chemical Society.

[27]  Richard A. Lerner,et al.  Proline-Catalyzed Direct Asymmetric Aldol Reactions , 2000 .

[28]  J. Tomasi,et al.  The IEF version of the PCM solvation method: an overview of a new method addressed to study molecular solutes at the QM ab initio level , 1999 .

[29]  Jacopo Tomasi,et al.  A new integral equation formalism for the polarizable continuum model: Theoretical background and applications to isotropic and anisotropic dielectrics , 1997 .

[30]  Robert G. Parr,et al.  Density Functional Theory of Electronic Structure , 1996 .

[31]  A. Becke Density-functional thermochemistry. III. The role of exact exchange , 1993 .

[32]  Parr,et al.  Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. , 1988, Physical review. B, Condensed matter.