The potential of "customizable units" to generate structural diversity for biological screenings is highlighted in this proof-of-concept synthesis of new peptides related to the potent antitumoral Sansalvamide A. Using L-4-hydroxyproline (Hyp) as a customizable unit in a linear parent peptide, an improved procedure for selective peptide modification was developed. A divergent Hyp scission-reductive amination process was carried out, affording five linear peptides with cationic residues, and notably, an N-alkyl moiety that affected the conformation of the peptide. After two steps (saponification and macrocyclization), sixteen differently N1-substituted linear and cyclic peptides were obtained. For the first time, the activity of the linear and cyclic compounds was compared. Not only some linear analogs but also cyclic compounds with scarcely studied cationic residues were active against MCF7 breast cancer line. Thus, the structural diversity generated from customizable units can be valuable in drug discovery.

Exciting developments in the site-selective modification of peptide backbones are allowing an outstanding fine-tuning of peptide conformation, folding ability, and physico-chemical and biological properties.

The selective manipulation of Hyp customizable units in DKP substrates allows the generation of a rigid scaffold with four tailor-made chains which are spatially-orientated. The key step is a domino radical scission-oxidation process which allows the generation ofN-substituted DKPs. The versatility of this methodology to produce scaffolds in high optical purity for material and drug discovery is described herein.

An efficient conversion of hydroxyproline "customizable" units into new amino acids with a variety of N-alkyl substituents is described. The process is versatile and can afford valuable N-methyl amino acids and N, O-acetals. In addition, it allows the introduction of N-homoallylic substituents and N-chains with terminal ester, ketone, or cyano groups. These chains could be used for peptide extension or conjugation to other molecules (e.g., by olefin metathesis, peptide ligation, etc.). The transformation is carried out in just two (for R = CH2OAc) or three steps (scission of the pyrrolidine ring, manipulation of the α-chain, and the N-substituent) under mild, metal-free conditions, affording products with high optical purity.

Resumen del poster presentado a la XXI Semana Cientifica “Antonio Gonzalez”, celebrada en La Universidad de La Laguna, Tenerife (Espana) del 24 al 27 de octubre de 2017.

Resumen del poster presentado a la XXI Semana Cientifica “Antonio Gonzalez”, celebrada en La Universidad de La Laguna, Tenerife (Espana) del 24 al 27 de octubre de 2017.

Sulfonic solids of different nature (alkyl, aryl and perfluoroalkyl sulfonic) are able to catalyze the dehydration of sorbitol under solvent free conditions at moderate temperature (130 degrees C) under vacuum and the esterification of isosorbide with carboxylic acids, either acetic or octanoic acids. Yields around 80% of isosorbide can be obtained from sorbitol with only 1 mol% catalyst after 24 h. Yields of dicarboxylates from isosorbide were in the range of 70-80% for diacetate and up to 97% for dioctanoate. The two-step one-pot process from sorbitol is highly efficient for isosorbide diacetate (up to 71% yield), whereas the esterification with octanoic acid is more sensitive to the presence of by-products (up to 57% yield).

Libraries of compounds containing unnatural amino acids or amino acid analogues were prepared from inexpensive substrates using sustainable processes [1–3]. [...]

The first steps of oseltamivir synthesis from quinic acid involve acetalization and ester formation. These reactions are catalyzed by either acids or bases, which may be accomplished by heterogeneous catalysts. Sulfonic solids are efficient acid catalysts for acetalization and esterification reactions. Supported tetraalkylammonium hydroxide or 1,5,7-triazabicyclo[4.4.0]dec-5-ene are also efficient base catalysts for lactone alcoholysis and in this work, these catalysts have been applied in two alternative synthetic routes that lead to oseltamivir. The classical route consists of an acetalization, followed by a lactonization, and then a lactone alcoholysis. This achieves a 66% isolated yield. The alternative route consists of esterification followed by acetalization and is only efficient when an acetone acetal is used.

The role of substituents in the acidolysis of several lignin models bearing a beta-O-4 linkage was studied through experimental (by using Nafion SAC-13 as a heterogeneous catalyst) and theoretical data (including transition state calculations). An equilibrium involving the protonation of either alpha-OH or beta-OH groups as well as the dehydration of the alpha-OH protonated form to yield a benzylic carbocation is assumed. Phenylacetaldehyde and phenol derivatives are the major reaction products for a number of lignin models, though other products have also been identified (such as enol ethers and coumaran derivatives). The high reactivity observed for lignin models bearing an ortho-methoxy group on the O-bound phenyl ring has been attributed to the methoxy anchimeric assistance to the benzylic position. On the other hand, the low formaldehyde yields observed in the acidolysis of some lignin models have been attributed to the hydrogen bond formation between the hydroxymethyl group and the base abstracting the beta-hydrogen of the carbocationic intermediate.

Our site-selective modification of serine or threonine units in peptides allows the generation of β-substituted dehydroamino acids, which increase peptide resistance to hydrolysis and may improve their biological properties. Both the terminal and internal positions can be modified, and different customizable units can be activated separately. Remarkably, high Z selectivity is achieved, even at internal positions. The conversion involves a one-pot oxidative radical scission/phosphorylation process by using the low-toxicity (diacetoxyiodo)benzene/iodine system as the scission reagent. The resulting α-amino phosphonates undergo a Horner-Wadsworth-Emmons reaction to produce the dehydroamino acid derivatives (in a Z/E ratio of usually >98:2) under mild and metal-free conditions.

Trabajo presentado en la IV International Conference on Antimicrobial Research ICAR, celebrada en Torremolinos (Espana) del 29 de junio al 1 de julio de 2016.

Trabajo presentado en la XX Semana Cientifica Antonio Gonzalez celebrada en La Laguna, Tenerife (Espana) del 4 al 7 de octubre de 2016.

Trabajo presentado en la IV International Conference on Antimicrobial Research ICAR, celebrada en Torremolinos (Espana) del 29 de junio al 1 de julio de 2016.