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The novel enantiopure synthesis of protected proline-cysteine analogs by means of 1,3-dipolar cycloaddition of homochiral thiazolines and azomethine ylides is described. The important role of the oxidation state of the sulfur atom of the dipolarophile in such reaction is demonstrated affecting strongly the regioselectivity and reactivity of the 1,3-dipolar cycloaddition. Mono-oxidized sulfur atom (sulfoxide group) and di-oxidized (sulfone group) led to 2,3 regio-addition whereas reactions starting from non-oxidized sulfur atom resulted in the 2,4 addition. Besides, sulfur oxidized thiazolines reacted smoothly upon heating in an organic solvent media but the non-oxidized sulfur thiazoline required metal catalysis. Diastereofacial selectivity was observed to be independent of the oxidation state of the sulfur atom but controlled by the bulky tert-butyl group at the thiazoline ring. The highly substituted and functionalized enantiopure pyrrolidine-thiazolidine bicyclic compounds are considered as novel (homo)cysteine-proline analogs with important properties to discover. Enantiopure proline-cysteine analogs were obtained by 1,3-dipolar cycloaddition between homochiral thiazolines and azomethine ylides. The reactivity and regioselectivity are controlled by the oxidation state of the thiazoline sulfur atom. Sulfoxide and sulfone groups led to 2,3 addition whereas reactions starting from the thioether group resulted in 2,4 addition. Diastereofacial selectivity is controlled by the bulky tert-butyl group at the thiazoline ring.

Proline is found in a cis conformation in proteins more often than other proteinogenic amino acids, where it influences structure and modulates function, being the focus of several high-resolution structural studies. However, until now, technical and methodological limitations have hampered the site-specific investigation of the conformational preferences of prolines present in poly proline (poly-P) homorepeats in their protein context. Here, we apply site-specific isotopic labeling to obtain high-resolution NMR data on the cis/trans equilibrium of prolines within the poly-P repeats of huntingtin exon 1, the causative agent of Huntington’s disease. Screening prolines in different positions in long (poly-P11) and short (poly-P3) poly-P tracts, we found that, while the first proline of poly-P tracts adopts similar levels of cis conformation as isolated prolines, a length-dependent reduced abundance of cis conformers is observed for terminal prolines. Interestingly, the cis isomer could not be detected in inner prolines, in line with percentages derived from a large database of proline-centered tripeptides extracted from crystallographic structures. These results suggest a strong cooperative effect within poly-Ps that enhances their stiffness by diminishing the stability of the cis conformation. This rigidity is key to rationalizing the protection toward aggregation that the poly-P tract confers to huntingtin. Furthermore, the study provides new avenues to probe the structural properties of poly-P tracts in protein design as scaffolds or nanoscale rulers.

The ortho-palladated phenylglycine derivative [Pd(µ-Cl)(C6H4C(H)(CO2Me)NH2-C,N)]2 (1) reacts with substituted styrenes R1C6H4CH=CH2 (2a–2f) to give two different compounds as a function of the reaction conditions. When the reaction was performed in chloroform under reflux, the stilbene derivatives [C6H4-1-(CH(CO2Me)(NH2))-2-(E)-(CH=CHC6H4R1)] (3a–3f) were obtained, but when the reaction was carried out in toluene under reflux, the 3-arylisoquinoline-1-carboxylates (4a–4f) were obtained instead. The method has distinct advantages over other methods in that it is simple and general, only one/two reaction steps are necessary to obtain the final product, the prefunctionalisation of the substrates is not mandatory and nor is the presence of ancillary ligands, and a regioselective mono-insertion of the alkenes is systematically observed.

We report here an alternative and practical method for the preparation of 1,2,3,4-tetrahydroisoquinoline-1-phosphonic acid and the first synthesis of 1,2,3,4-tetrahydroisoquinoline-1-H-phosphinic and 1,2,3,4-tetrahydroisoquinoline-1-phenylphosphinic acids through Kabachnik–Fields and aza-Pudovik reaction. This methodology does not require any metallic catalyst and proceeds under mild reaction conditions.

The stereoselective synthesis of truxillic bis-amino esters from polyfunctional oxazolones is reported. The reaction of 4-((Z)-arylidene)-2-(E)-styryl-5(4H)-oxazolones 2 with Pd(OAc)2 resulted in ortho-palladation and the formation of a dinuclear open-book complexes 3 with carboxylate bridges, where the Pd atom is C^N bonded to the oxazolone. In 3 the two exocyclic C=C bonds of the oxazolone are in a face-to-face arrangement, which is optimal for their [2 + 2] photocycloaddition. Irradiation of dimers 3 in CH2Cl2 solution with blue light (465 nm) promoted the chemo- and stereoselective [2 + 2] photocycloaddition of the exocyclic C=C bonds and the formation of cyclobutane-containing ortho-palladated complexes 4. Treatment of 4 with CO in a MeOH/NCMe mixture promoted the methoxycarbonylation of the palladated carbon and the release of the corresponding ortho-functionalized 1,3-diaminotruxillic bis-amino esters 5 as single isomers.