Late-stage C-H Functionalization of Tryptophan-Containing Peptides with Thianthrenium Salts: Conjugation and Ligation.

Bioorthogonal late-stage diversification of structurally complex peptides bears enormous potential for drug discovery and molecular imaging, among other applications. Herein, we report on a palladium-catalyzed C-H arylation of tryptophan-containing peptides with readily accessible and modular arylthianthrenium salts. Under exceedingly mild reaction conditions, the late-stage diversification of structurally complex peptides was accomplished. The tunability and ease of preparation of arylthianthrenium salts allowed the expedient stitching of tryptophan-containing peptides with drug, natural product, and peptidic scaffolds by forging sterically congested biaryl linkages. The robustness of the palladium catalysis regime was reflected by the full tolerance of a plethora of sensitive and coordinating functional groups. Hence, our manifold enabled efficient access to highly decorated, labelled, conjugated, and ligated linear and cyclic peptides.

Straightforward Synthesis of Highly Functionalized Indanes and Tetralines through Ene-Cyclopropene Rearrangement Mediated by Ruthenium.

Ene-cyclopropenes give functionalized indanes and tetralines in the presence of ruthenium dimeric catalysts. This reaction involves the cyclopropene opening by the metal catalysts with a different regioselectivity respective to gold chlorides and produces totally different products than when using semisandwich ruthenium complexes. Here, the process leads to a bridged 7-oxanorbornene-type intermediate that is converted into a functionalized aromatic ring through deoxygenative aromatization. Alternative reaction pathways occur with substrates with no possible aromatization.

One Pot Synthesis of Spirocycles and Cyclopropa[b]pyrans by Alkenylation-Rearrangement of Cyclopropenes.

A one pot alkenylation followed by a stereoselective Alder-ene cycloisomerization of cyclopropenes give (aza)spiro[2.4]heptanes and spiro[2.5]octanes in high yields. Total trans diastereoselectivity is achieved for spiro[2.4]heptanes if the cyclopropene is monosubstituted in C3. When an α,ß-unsaturatedcarbonyl-containing bromide is used, an alternative cyclization takes place giving cyclopenta[c]cyclopropa[b]pyrans.

Synthesis and Evaluation of Novel Iminosugars Prepared from Natural Amino Acids.

Cyclopropanated iminosugars have a locked conformation that may enhance the inhibitory activity and selectivity against different glycosidases. We show the synthesis of new cyclopropane-containing piperidines bearing five stereogenic centers from natural amino acids l-serine and l-alanine. Those prepared from the latter amino acid may mimic l-fucose, a natural-occurring monosaccharide involved in many molecular recognition events. Final compounds prepared from l-serine bear S configurations on the C5 position. The synthesis involved a stereoselective cyclopropanation reaction of an α,ß-unsaturated piperidone, which was prepared through a ring-closing metathesis. The final compounds were tested as possible inhibitors of different glycosidases. The results, although, in general, with low inhibition activity, showed selectivity, depending on the compound and enzyme, and in some cases, an unexpected activity enhancement was observed.

Intramolecular Diels-Alder Reaction of Cyclopropenyl Vinylarenes: Access to Benzonorcarane Derivatives.

Intramolecular Diels-Alder vinylarene reaction (IMDAV) is a [4 + 2] cycloaddition that employs styrene derivatives as conjugated dienes, whose poor reactivity arises from the required loss of aromaticity, which is recovered by a subsequent [1,3]-H shift. Herein, we describe the use of cyclopropene as a dienophile, harnessing its strain energy to drive the IMDAV reaction. Benzonorcarane scaffolds form in good yields, excellent stereoselectivity, and broad functional tolerance. Theoretical calculations and NMR studies have revealed significant mechanistic insights.

Amino Acid-Based Synthesis and Glycosidase Inhibition of Cyclopropane-Containing Iminosugars.

Synthesis of four iminosugars fused to a cyclopropane ring is described using l-serine as the chiral pool. The key steps are large-scale preparation of an α,ß-unsaturated piperidinone followed by completely stereoselective sulfur ylide cyclopropanation. Stereochemistry of compounds has been studied by nuclear Overhauser effect spectroscopy (NOESY) experiments and 1H homonuclear decoupling to measure constant couplings. The activity of these compounds against different glycosidases has been evaluated. Although inhibition activity was low (compound 8a presents a (K i) of 1.18 mM against ß-galactosidase from Escherichia coli), interestingly, we found that compounds 8a and 8b increase the activity of neuraminidase from Vibrio cholerae up to 100%.