β-Amino Acid Organocatalysts in the Asymmetric Michael Addition of Isobutyraldehyde to N-Substituted Maleimides

Asymmetric Michael additions of carbonyl compounds to N-substituted maleimides are among the most convenient reactions to prepare optically pure succinimide building blocks. Although a few β-amino acids were found to be highly efficient organocatalysts in the addition of α-branched aldehydes, the effect of their structure on the results of these reactions has not yet been investigated. In the present study, we disclose several unexpected and interesting structural effects of aliphatic and cycloaliphatic β-amino acids obtained in the enantioselective conjugate addition of isobutyraldehyde to N-benzylmaleimide. The dependence of the sense of the enantioselectivity on the bulkiness of the substituent on the β-carbon atom, the beneficial spatial arrangements of the functional groups in cis isomers with cyclohexane scaffold and the inversion of the enantioselectivity depending on the absence of a base additive observed with some trans isomers are unprecedented findings. The minor influence of the nitrogen substituent of the maleimide ring on both the reaction rate and the enantioselectivity was also evidenced using alicyclic β-amino acid prepared from an easily available terpene derivative

Béta-aminosavaktól a biomimetikus foldamerekig és bioaktív építőelemekig = From the Beta-Amino Acid Toolkit to Biomimicking Foldamers and Bioactive Building Blocks

A foldamerek gyógyszerkémiájának területén a következő fontosabb eredményeket értük el. 1. Összefüggést állapítottunk meg a peptidomimetikus szekvenciák sztereokémiai mintázata és az indukált másodlagos szerkezet között. Kimutattuk, hogy a homokiralitás nem szükséges feltétele az önrendeződésnek. Meghatároztuk a hélixek kialakításának általános feltételeit és egy sztereokémiai mintázati módszert javasoltunk a hélixek de novo tervezéséhez. 2. Elsőként mutattuk meg, hogy a ?-peptid foldamerek önasszociációja nanostrukturált rendszerek (fibrillumok és vezikulák) kialakulásához vezethet másodlagos szerkezettől függő módon. 3. Új módszert javasoltunk egy ?-hélix mimetikum ?-peptid kialakítására monoterpén-vázas ?-aminosavak alkalmazásával. 4. Egy általános, oldalláncoktól független módszert vezettünk be a foldamerek másodlagos szerkezetének vizes közegben történő stabilizálására. 5. Monoterpén-vázas ?-aminosav származékokat állítottunk elő régio- és sztereoszeketíven. A vegyületek igéretesek farmakológiai szempontból. 6. Monoterpén-vázas királis aminodiolokat szintetizáltunk, és a vegyületeket spirooxazolin és spirooxazolidin enantiomerek régioszelektív gyűrűzárással történő szintézisében alkalmaztuk. 7. Feszített oldalláncú ?-aminosav enantiomereket állítottunk elő régio- és sztereoszelektíven. Ezeket konformációsan gátolt triciklusos ?-laktám enantiomerek szintézisében használtuk fel, amelyet négycentrumos három-komponensű Ugi-reakcióval valósítottunk meg. | In the field of pharmaceutical chemistry of foldamers, the contributions achieved are as follows. 1. Relationship between the stereochemical pattern of the peptidomimetic sequences and the foldamer secondary structures was established. We showed that homochirality is not a necessary condition for the self-organization. The general requirements of helix formation have been determined and a stereochemical patterning method has been proposed for the de novo helix design. 2. It has been shown for the first time, that the self-assembly of ?-peptide foldamers can lead to nanostructured systems (fibrils and vesicles) in a secondary structure-dependent way. 3. A method has been proposed to induce the formation of an ?-helix mimetic ?-peptide by using monoterpene-based ?-amino acids. 4. A general side-chain independent method was devised to stabilize the foldameric secondary structures in aqueous medium. 5. Regio- and stereoselective synthesis of the enantiomers of monoterpene-based ?-amino acid derivatives having promising pharmacological applications. 6. Synthesis of monoterpene-based chiral aminodiols and their application in synthesis of enantiomeric spirooxazolines and spirooxazolidines by the regioselective ring closure. 7. Regio- and stereoselective synthesis of constrained enantiomeric ?-amino acid derivatives and their application in synthesis of conformationally constrained tricyclic ?-lactam enantiomers via Ugi four-centre three-component reactions

Stereoselective Synthesis and Antiproliferative Activity of Steviol-Based Diterpene 1,3-Aminoalcohol Regioisomers

A series of novel diterpene-type 1,3-aminoalcohols and their regioisomers have been synthesised from natural stevioside in a stereoselective manner. The key intermediate β-keto alcohol was prepared using Wagner–Meerwein rearrangement of the epoxide derived from steviol methyl ester. The primary aminoalcohol was formed via Raney-nickel-catalysed hydrogenation of an oxime, and a versatile library of aminoalcohols was synthesised using a Schiff base with the primary amines. The aminoalcohol regioisomers were prepared from the mesylate of the β-keto alcohols. The corresponding primary aminoalcohol was formed via the palladium-catalysed hydrogenation of hydroxyl-azide, and click reactions of the latter were also carried out. The new compounds were characterised using 1D- and 2D-NMR techniques and HRMS measurements. The in vitro investigations showed high inhibition of cell growth in human cancer cell lines (HeLa, SiHa, A2780, MCF-7 and MDA-MB-231) in the case of naphthalic N-substituted derivatives. The antiproliferative effects were assayed using the MTT method

Stereoselective Synthesis and Application of Gibberellic Acid-Derived Aminodiols

A series of gibberellic acid-based aminodiols was designed and synthesized from commercially available gibberellic acid. Exposure of gibberellic acid to hydrochloric acid under reflux conditions resulted in aromatization followed by rearrangement to form allo-gibberic acid. The key intermediate, ethyl allo-gibberate, was prepared according to literature methods. Epoxidation of key intermediate and subsequent ring-opening of the corresponding epoxide with different nucleophiles resulted in N-substituted aminodiols. The regioselective ring closure of N-benzyl-substituted aminodiol with formaldehyde was also investigated. All aminodiol derivatives were well characterized using modern spectroscopic techniques and evaluated for their antiproliferative activity against a panel of human cancer cell lines. In addition, structure–activity relationships were examined by assessing substituent effects on the aminodiol systems. The results indicated that aminodiols containing aromatic rings on their nitrogen substituents displayed significant cytotoxic effects. Among these agents, N-naphthylmethyl-substituted aminodiols were found to be the most potent candidates in this series. One of these molecules exhibited a modest cancer selectivity determined by non-cancerous fibroblast cells. A docking study was also made to exploit the observed results

Sculpting the beta-peptide foldamer H12 helix via a designed side-chain shape

The long-range side-chain repulsion between the (1R, 2R, 3R, 5R)-2- amino-6,6-dimethyl-bicyclo[3.1.1]-heptane-3-carboxylic acid (trans-ABHC) residues stabilize the H12 helix in beta-peptide oligomers