Kinetic resolution using nucleophilic catalysts

The synthesis of enantiomerically pure compounds has become one of the most important fields of organic synthesis and high enantiomeric purity is a requirement in the synthesis of chiral pharmaceuticals. Organocatalyzed kinetic resolutions (KR) of racemic substrates to afford enantiopure compounds in high enantioselectivity and good yield have gained popularity within the synthetic community over the last two decades. Secondary alcohols are an important class of readily derivatizable compounds that can be incorporated into a variety of synthetic strategies. Many methodologies have been developed for the asymmetric synthesis of these compounds, among them the non-enzymatic resolution using a planar chiral DMAP catalyst ()-1. Fu and co-workers have shown the efficiency of ()-1 at resolving aryl alkyl carbinols, allylic and propargylic alcohols.

Recently, we demonstrated that the catalyst ()-1 catalysed the resolution for a range of aromatic 1,2-azidoalcohols with good selectivity factors (up to S=45) and high enantiomeric excess (up to 99% ee) of the remaining alcohol. In addition, we have also successfully resolved b-hydroxyphosphonates and b-hydroxyesters yielding the corresponding alcohols in excellent enantiomeric excess (up to 99% ee) and with excellent selectivity factors (up to 107).

This projects aim to develope non-enzymatic kinetic resolutions of alcohol and amines using small organic catalyst and to combine them in racemization processes to achieve practical Dynamic Kinetic Resolution. In our effort to expand the applicability of this planar chiral DMAP catalyst, we studied the KR of sec-alcohols that contains an additional functional group in the alkyl moiety.

Recent publications

A Mechanistic Investigation of the Kinetic Resolution of Secondary Aromatic Alcohols Using a Ferrocene-Based Planar Chiral 4-(Dimethylamino)pyridine Catalyst  L. Mesas-Sánchez, P. Dinér*, Chem. Eur. J., 2015, 21(14), 5623–5631.

Access to optically pure β-hydroxy esters via non-enzymatic kinetic resolution by a planar-chiral DMAP catalyst  

Alba E. Díaz-Álvarez, Laura Mesas-Sánchez, P. Dinér*Molecules2014, 9(19), 14273-14291.

Kinetic resolution of 2-hydroxy-2-aryl-ethylphosphonates by a non-enzymatic acylation catalyst

L. Mesas-Sánchez, A. E. Díaz-Álvarez, P. Koukal, P. Dinér*, Tetrahedron2014, 70(24), 3807-3811.

Non-enzymatic kinetic resolution of 1,2-azidoalcohols using a planar chiral DMAP catalyst   

L. Mesas-Sánchez, Alba E. Díaz-Álvarez, P. Dinér*, Tetrahedron2013, 69(2), 753-757. 

Kinase inhibitors

Protein kinases have a crucial role in most, if not all, signaling pathways and regulate diverse cellular functions, such as cell-cycle progression, apoptosis, metabolism, differentiation, cell morphology and migration, and secretion of cellular proteins.

This project aims to design, synthesize and biological evaluate inhibitors related to kinases involved in cancer.  Recently, we have shown that it is possible to reduce the core of the scaffold from a five- or six-membered ring to a double bond and still keep the strong inhibitory effect observed for previous inhibitors with the 4-fluoro-phenyl/pyridinyl motif. The synthesized azastilbene compounds were found to inhibit the p38-kinase with IC50-values down to about 100 nM.

Photo-switchable kinase inhibitors

Protein kinases have a crucial role in most, if not all, signaling pathways and regulate diverse cellular functions, such as cell-cycle progression, apoptosis, metabolism, differentiation, cell morphology and migration, and secretion of cellular proteins. The understanding of cellular signal transduction is restricted to the wiring schemes of signaling pathways. Little is known about the dynamic operation and time-dependent parameters for signaling output. The use of fast-acting, selective, cell-permeable inhibitors enables a systematic investigation of the time-dependent parameters for signaling output. Therefore, it would be interesting to develop highly selective, cell-permeable, and fast-acting inhibitors of individual kinases that would allow for the systematic investigation of the cellular function of a kinase in real time.

The aim of this project is to design inhibitors that can be turned on and off by the irradiation of light, and, thereby also turn on and off the signaling dependent on an activated kinase. The designed inhibitors will be based on the principle that some molecules can exists in two different isomers and the two isomers that can interconvert between each other by the application of light at a specific wavelength. The two different isomers are designed to have different binding affinity to the ATP binding site, i.e. one of isomers is an efficient inhibitor and the other isomer is an inhibitor with weak binding.

Recent publications

Selective inhibition of RET mediated cell proliferation in vitro by the kinase inhibitor SPP86

J. P. Alao*, S. Michlikova, P. Dinér, M. Grøtli, P. Sunnerhagen, BMC cancer2014, 14(1), 853.

A Single-Cell Study of a Highly Effective Hog1 Inhibitor for in Situ Yeast Cell Manipulation

C. Hamngren Blomqvist, P. Dinér, M. Grøtli, M., Goksör, C. B. Adiels*, Micromachines20145, 81-96.

Azastilbenes: A cut off to p38 MAPK inhibitors

J. Poon, J.-P. Alao, P. Sunnerhagen, P. Dinér*, Org. Biomol. Chem.2013, 11 (27), 4526-4536.

Preparation of 3-Substituted-1-Isopropyl-1H-Pyrazolo[3,4-d]Pyrimidin-4-Amines as RET Kinase Inhibitors

P. Dinér, J. P. Alao, J. Söderlund, P. Sunnerhagen, M. Grøtli*, J. Med. Chem., 2012, 55(10), 4872-48-76.

Design, Synthesis and Biological Evaluation of Chromone-based p38 MAP Kinase Inhibitors

Dyrager, C.; Nilsson Möllers, L.; Kjäll, L.; Alao, J.; Dinér, P.; Wallner, F.; Sunnerhagen, P.; Grotli, M.*, J. Med. Chem.201154(20), 7427–7431. 

Design, synthesis, and characterization of a highly effective Hog1 inhibitor: a powerful tool for analyzing MAP kinase signaling in yeast

P. Dinér, J. Veide Vilg, J. Kjellén, I. Migdal, T. Andersson, M. Gebbia, G. Giaever, C. Nislow, S. Hohmann, R. Wysocki, M. J. Tamás, M. Grøtli*, PlosOne2011, 6(5), e20012. 

Page responsible:Peter Dinér
Belongs to: Department of Chemistry
Last changed: Oct 09, 2015