Catalytic asymmetric synthesis of heterocycles

PhD ceremony: Mr. J.F. Teichert, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Title: Catalytic asymmetric synthesis of heterocycles

Promotor(s): prof. B.L. Feringa

Faculty: Mathematics and Natural Sciences

The research carried out in this thesis was directed towards the development of new, catalytic asymmetric transformations for the efficient and selective synthesis of heterocyclic compounds. These molecules are important synthetic intermediates for the preparation of biologically active compounds, such as in pharmaceuticals.

The methodologies used in this work comprise asymmetric copper-catalyzed allylic substitution, copper-catalyzed conjugate addition and iridium-catalyzed allylic substitutions.

Through copper-catalyzed allylic substitution reactions chiral nitrogen-containing heterocycles are available in combination with ring-closing metathesis. One important feature of these reactions is that it opens up a variable entry to a number of different ring sizes.

Employing copper-catalyzed conjugate addition reactions of Grignard reagents on coumarin derivatives, the corresponding conjugate addition products are available in high yields and enantioselectivities. It was found that the addition products serve as versatile synthetic intermediates, as they could be converted in situ into previously unavailable chiral phenolic esters and amides.

One of the highlights of this work is represented by the development of the first intramolecular asymmetric iridium-catalyzed allylic amidation. This new transformation opens up a synthetic pathway towards chiral tetrahydroisoquinolines and chiral saturated nitrogen heterocycles. Chiral tetrahydroisoquinolines are key structural features of a vast number of biologically active products. Previously, very few synthetic entries towards these products existed.