Jonas Brånalt

Synthesis of enantiomerically pure cis and trans 2-aminocyclopentanecarboxylic acids. Use of proline replacements in potential HIV-protease inhibitors

The synthesis of the four diastereomeric 2-aminocyclopentanecarboxylic acids, their use as replacements for proline in potential HIV protease inhibitors containing a hydroxyethylamine dipeptide isostere and the evaluation of the biological activity of these is described.

Synthesis of Potential Thrombin Inhibitors. Incorporation of Tartaric Acid Templates as P2 Proline Mimetics

With the objective to prepare novel non-peptidic thrombin inhibitors, bioisosteres of the inhibitory tripeptide D-Phe-Pro-Arg chain have been examined. Thus, the P1 Arg was replaced with p-amidinobenzylamine, an elongated homologue of the same and with 2,5-dichloro benzylamine. The P2-P3, D-Phe-Pro, was replaced with a novel tartaric acid template coupled to a series of readily available, mainly lipophilic, amines. Some of these compounds exhibit promising thrombin inhibition activity in vitro, IC(50 ) approximately 5.9 microM.

Regio- and Stereoselective Synthesis of Functionalized Cyclopentene Derivatives via Mizoroki–Heck Reactions

Pd(0)-catalyzed Mizoroki-Heck alkenylations and arylations of protected aminocyclopentenes, prepared in a few steps from Vince lactam, afforded functionalized cyclopentenes in high yields and stereoselectivities. DFT calculations were performed to rationalize the high diastereoselectivities. Functionalized cyclopentene products were transformed into valuable chiral building blocks, such as cyclic γ-amino acids and carbocyclic nucleoside precursors.

Unexpected Retroaldol-Aldol Reaction during O-Alkylation of Hydroxylated Vince Lactam Derivatives

The unexpected retroaldol-aldol reaction during O-alkylation of a β-hydroxy lactam was found to be highly dependent on the temperature and shows a remarkable solvent effect. In DMF, O-alkylation is faster than retroaldol-aldol rearrangement giving exclusively products with retention of configuration. In THF, O-alkylation is slower than rearrangement, giving selectively products with inversion of stereochemistry. In DMSO, a retroaldol reaction followed by fast intramolecular proton transfer occurs to give the ring-opened aldehyde.

Selective Synthesis of Spirooxindoles by an Intramolecular Heck–Mizoroki Reaction

We report a highly diastereoselective synthesis of cyclopentene-spirooxindole derivatives via an intramolecular Heck-Mizoroki reaction using aryl bromides as precursors. The reactions were performed under dry conditions or in a DMF-water system. This protocol can be useful to introduce several functionalities to the aromatic nucleus of the spirooxindoles. DFT calculations were performed to rationalize the high antiselectivity. A functionalized spiroproduct was transformed into a cyclic amino acid derivative.

Macrocyclic Prodrugs of a Selective Nonpeptidic Direct Thrombin Inhibitor Display High Permeability, Efficient Bioconversion but Low Bioavailability

The only oral direct thrombin inhibitors that have reached the market, ximelagatran and dabigatran etexilat, are double prodrugs with low bioavailability in humans. We have evaluated an alternative strategy: the preparation of a nonpeptidic, polar direct thrombin inhibitor as a single, macrocyclic esterase-cleavable (acyloxy)alkoxy prodrug. Two homologous prodrugs were synthesized and displayed high solubilities and Caco-2 cell permeabilities, suggesting high absorption from the intestine. In addition, they were rapidly and completely converted to the active zwitterionic thrombin inhibitor in human hepatocytes. Unexpectedly, the most promising prodrug displayed only moderately higher oral bioavailability in rat than the polar direct thrombin inhibitor, most likely due to rapid metabolism in the intestine or the intestinal wall. To the best of our knowledge, this is the first in vivo ADME study of macrocyclic (acyloxy)alkoxy prodrugs, and it remains to be established if the modest increase in bioavailability is a general feature of this category of prodrugs or not.