Abstract
The development of strategies for the transformation of olefins represents a highly rewarding
challenge in chemical synthesis, due to the versatile reactivity and widespread accessibility of
this functionality. The reactions of olefins with heteroatom-containing electrophiles result both
in carbon–carbon bond formation and introduction of heteroatoms in the molecular skeleton,
thus allowing to convert the relative structural simplicity of olefins into complex structures.
The following work describes the catalytic, asymmetric, intermolecular reaction between aryl
olefins and paraformaldehyde, known as the Prins reaction, enabled by the development of
sterically-confined imino-imidodiphosphate (iIDP) Brønsted acid catalysts. By careful fine-
tuning the catalyst structure, a great number of aryl olefins could be transformed, covering a
broad range of electron density on the alkene moiety. In this way, enantiomerically-enriched
1,3-dioxanes were efficiently prepared from inexpensive and commercially available reagents.
The obtained enantioenriched 1,3-dioxane rings could also be transformed to the
corresponding optically-active 1,3-diols. These compounds constitute valued intermediates for
the synthesis of multiple pharmaceutically-relevant molecules, such as Fluoxetine®,
Dapoxetine® and Tomoxetine®, among others. Additionally, the developed catalytic,
asymmetric Prins reaction was successfully utilized for the synthesis of several deuterium-
containing enantioenriched 1,3-dioxanes, where the position and degree of deuteration could
be controlled by proper choice of the starting materials.
Mechanistic studies (isotope-labeling experiments and computations) showed that the reaction
using the confined iIDP as catalyst proceeds by a highly asynchronous, concerted pathway,
whereas a catalyst with a more open active site, such as p-toluenesulfonic acid, shifts the
reaction to take place by a stepwise mechanism.
Taken together, the work described in this thesis represents a new tool in synthetic chemistry
for the streamlined formation of structural complexity from rather simple, highly available
starting materials. It also opens up the field for further contributions toward a more general
intermolecular reaction of olefins and aldehydes.
