Final Report Summary - MODDESGNORGCAT (Modular design of organocatalysts by combination of subunits effective in complementary catalytic mechanisms)
In Annex I of the Grant Agreement corresponding to this research project, the research activities to be carried out during the development of this agreement are ascribed to the field of organocatalysis. These organocatalysts will be inspired in the structure of real enzymes and based on computational methods.
The funding provided by the research project has allowed us access to the computational facilities (either hardware or software) that constitutes a valuable tool in the development of new organocatalysts, as well as to understand how organocatalysts work.
During this time, we have been also able to develop new organocatalysts which combines scaffolds able to mimic structures present in natural enzymes. One of these structures, known as oxyanion hole, was previously studied by Luis Simón during his postdoctoral stay in the University of Cambridge under the supervision of Jonathan M. Goodman. However, after the research project was granted, one article put some doubts on the results and conclusions of this original work. Luis Simón and Jonathan Goodman have been able to refute these objections with the help of the funding provided by the reintegration grant, and a manuscript with all these new results has been prepared for its submission.
Some of the catalysts developed combine an oxyanion hole mimic with other catalytic groups. In this regard, a chiral sulfoxide catalysts with very good catalytic activity in the Michael addition of pyrrolidine to alpha,beta unsaturated ketone was prepared; the chiral resolution of this receptor was achieved by an ingenious methodology based on their supramolecular properties and its epimerisation in the presence of a chiral guests. The manuscript describing this receptor and its chiral resolution was published in Organic and Biomolecular Chemistry, and has become one of the 10 most highly accessed online papers of this journal in its publication year.
Proline and its role in the catalysis of aldol reaction is a paradigmatic example of an organocatalyst. Although proline is usually considered to emulate the action of aldolase enzymes, it is clear than the structure of these enzymes and aldolases are very different. In an attempt to prepare organocatalysts with a closer resemblance to aldolases, we combined proline with a chromene-derived carboxylic acid. The results were included in the Master degree work of David G. Seisdedos. Since these reactions were difficult to interpret in the framework of the commonly admitted reaction mechanism of the proline-catalysed aldol reaction, we started to research the reaction mechanism of aldol reactions catalysed by prolinamides. We were able to identify that imidazolidinone intermediates could have an important role in this reaction. These results, which contribute to an intense scientific debate regarding the role of oxazolidinone (an analog to imidazolidinone) intermediates, has been published in Organic and Biomolecular Chemistry.
1,2-Cyclohexane-diamine is another interesting scaffold for the design of organocatalysts. We have developed a new efficient and versatile method for the synthesis of catalysts containing this structure, published recently in the Journal of Organic Chemistry. Using these procedures, we expect to incorporate 1,2-cyclohexane-diamine scaffold into the structure of organocatalysts which could also combine oxyanion hole mimics.
Luis Simón is also collaborating with Dr Jonathan M. Goodman in clarifying the mechanism of another important king of organocatalysts: BINOP. They have obtained results that allowed to build a model to predict the sense and degree of the enantioselectivity obtained. They have also make a study of the reliability of the computational methods usually employed in these kind of calculations, which results are currently been collected to prepare a new article.
The funding provided by the research project has allowed us access to the computational facilities (either hardware or software) that constitutes a valuable tool in the development of new organocatalysts, as well as to understand how organocatalysts work.
During this time, we have been also able to develop new organocatalysts which combines scaffolds able to mimic structures present in natural enzymes. One of these structures, known as oxyanion hole, was previously studied by Luis Simón during his postdoctoral stay in the University of Cambridge under the supervision of Jonathan M. Goodman. However, after the research project was granted, one article put some doubts on the results and conclusions of this original work. Luis Simón and Jonathan Goodman have been able to refute these objections with the help of the funding provided by the reintegration grant, and a manuscript with all these new results has been prepared for its submission.
Some of the catalysts developed combine an oxyanion hole mimic with other catalytic groups. In this regard, a chiral sulfoxide catalysts with very good catalytic activity in the Michael addition of pyrrolidine to alpha,beta unsaturated ketone was prepared; the chiral resolution of this receptor was achieved by an ingenious methodology based on their supramolecular properties and its epimerisation in the presence of a chiral guests. The manuscript describing this receptor and its chiral resolution was published in Organic and Biomolecular Chemistry, and has become one of the 10 most highly accessed online papers of this journal in its publication year.
Proline and its role in the catalysis of aldol reaction is a paradigmatic example of an organocatalyst. Although proline is usually considered to emulate the action of aldolase enzymes, it is clear than the structure of these enzymes and aldolases are very different. In an attempt to prepare organocatalysts with a closer resemblance to aldolases, we combined proline with a chromene-derived carboxylic acid. The results were included in the Master degree work of David G. Seisdedos. Since these reactions were difficult to interpret in the framework of the commonly admitted reaction mechanism of the proline-catalysed aldol reaction, we started to research the reaction mechanism of aldol reactions catalysed by prolinamides. We were able to identify that imidazolidinone intermediates could have an important role in this reaction. These results, which contribute to an intense scientific debate regarding the role of oxazolidinone (an analog to imidazolidinone) intermediates, has been published in Organic and Biomolecular Chemistry.
1,2-Cyclohexane-diamine is another interesting scaffold for the design of organocatalysts. We have developed a new efficient and versatile method for the synthesis of catalysts containing this structure, published recently in the Journal of Organic Chemistry. Using these procedures, we expect to incorporate 1,2-cyclohexane-diamine scaffold into the structure of organocatalysts which could also combine oxyanion hole mimics.
Luis Simón is also collaborating with Dr Jonathan M. Goodman in clarifying the mechanism of another important king of organocatalysts: BINOP. They have obtained results that allowed to build a model to predict the sense and degree of the enantioselectivity obtained. They have also make a study of the reliability of the computational methods usually employed in these kind of calculations, which results are currently been collected to prepare a new article.