Current Topics in Medicinal Chemistry - Volume 14, Issue 10, 2014

This review will describe the recent advances in the synthesis of C-nucleosides with inhibitory activity of inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the biosynthesis of guanine nucleotides. The review will cover synthetic approaches of structural analogues showing modifications in the furanose ring as well as in the heterocyclic base. Heterocyclic sugar nucleoside analogues in which the furanose ring has been replaced by a different heterocyclic ring including aza analogues, thioanalogues as well as dioxolanyl and isoxazolidinyl analogues are also considered.

α-Methylisoserine, a chiral acyclic quaternary β-amino acid, has been used to mimic secondary structures, when it is incorporated in a homogeneous β2,2-dipeptide. In particular, the observed folded conformations in aqueous solution can be regarded as mimics of β-turn.

This review is dedicated to enantioselective methods for the generation of carbohydrate-based lead compounds for drug research. Selected examples encompassing imino sugars, bicyclic imino sugar-type alkaloids such as castanospermine, swainsonine, or alexine, as well as macrolide glycosides are covered and discussed.

Thiazoline and thiazole heterocycles are privileged motifs found in numerous peptide-derived natural products of biological interest. During the last decades, the synthesis of optically pure building blocks has been addressed by numerous groups, which have developed a plethora of strategies to that end. Efficient and reliable methodologies that are compatible with the intricate and capricious architectures of natural products are a must to further develop their science. Structure confirmation, structure-activity relationship studies and industrial production are fields of paramount importance that require these robust methodologies in order to successfully bring natural products into the clinic. Today’s chemist toolbox is assorted with many powerful methods for chiral thiazoline and thiazole synthesis. Ranging from biomimetic approaches to stereoselective alkylations, one is likely to find a suitable method for their needs.

In recent years, peptidomimetics have gained enormous importance in drug design aiming to achieve increased drug metabolic stability and higher selectivity. In the field of peptidomimetics, β-peptides incorporating β2- and β3-amino acids (the higher homologs of natural α-amino acids) provide a powerful method for the synthesis of peptidomimetics with particular secondary structures. In this regard, 1,2,3-triazole-modified peptidomimetics can act as effective peptide surrogates, and therefore have gained considerable attention. In the present report, 1,4-disubstituted 1,2,3-triazoles attached to β-amino acids were prepared selectively from the corresponding alkynyl-β2-amino acids according to Huisgen’s copper-catalyzed 1,3-dipolar cycloaddition (CuAAC), under mild conditions and with very high efficiency. Different azide derivatives, including some incorporating α-amino acids, were employed in this cycloaddition reaction. The enantiopure compounds were obtained via diastereomeric salt formation with chiral adjuvants, and subsequent separation.

This review highlights the biological importance of many polysubstituted nitro-prolines and -pyrrolidines. Their preparation using asymmetric 1,3-dipolar cycloadditions of azomethine ylides with nitroalkenes using diastereoselective and enantioselective strategies is described remarking the scope and main features of each one.

This review deals with stereoselective issues in PPAR ligands some of which are in clinical use for treating certain metabolic disorders. After a short introduction of these nuclear receptor and their agonists, some cases of enantioselective separations are reported. The main part concerns stereoselective synthesis first starting with asymmetric synthesis from chiral precursors followed by what we refer to as “true” enantioselective methods. Some examples are discussed in detail for each particular heading.

(+)-Lentiginosine, a natural trans-1,2-dihydroxyindolizidine belonging to the class of iminosugars, is a potent inhibitor of amyloglucosidase, and a good inhibitor of Hsp90. The non-natural enantiomer, (–)-lentiginosine, induces apoptosis on tumor cells of different origin and is poorly cytotoxic towards non-transformed cells. The significant biological activity of these compounds has resulted in the development of many synthetic approaches for their preparation. This review is an update of a previous survey and summarizes the most recent achievements on biological studies as well as total syntheses of lentiginosine and trans-1,2-dihydroxyindolizidine analogues.

Many pharmaceutical agents include piperazines or oxopiperazines as part of their core structures. The presence of substituents on these heterocycles has a significant influence on the biological activity, thus the search for efficient routes to control the substitution at different ring positions might have a crucial impact, especially to promote the use of such scaffolds in SAR studies. Many research groups have been engaged in the stereoselective synthesis of polysubstituted piperazines and oxopiperazines and in the majority of cases the stereochemistry of the final compounds is dependent on the starting material configuration. In the present minireview we have summarized some of the most significant approaches towards the stereoselective synthesis and functionalization of substituted piperazines and oxopiperazines, with a particular focus on our own contributions mainly based on readily available natural amino-acids as “chiral pool” starting materials. An efficient and scalable route to orthogonally protected 2-oxopiperazines has been developed using the corresponding diamines as key intermediates: diastereoselective elaboration of the resulting heterocycles was possible by metalation and reaction with electrophiles, leading to anti 3,5-disubstituted-oxopiperazines, in agreement with the model for a conventional 1,3-asymmetric induction. Both piperazines and tetrahydropyrazines could be prepared via LiAlH4-mediated reduction of 2-oxopiperazines, depending on reaction conditions. Finally, the diastereoselective synthesis of cyclopropane- containing analogs 2,5-diaza-bicyclo[4.1.0]heptanes was demonstrated by application of the classic Simmons-Smith reaction on enantiomerically enriched dihydro-2H-pyrazines.

The Michael reaction of bis(phenylsulfonyl)methane with α,β-unsaturated aldehydes in the presence of catalytic amounts of a chiral secondary amine is presented. This transformation proceeds in good to excellent yields furnishing the corresponding Michael adducts in excellent enantioselectivities. Furthermore, other chiral building blocks are accessible from the obtained adducts by carrying out selective manipulation of the functional groups present at their structure, being possible to obtain a wide variety of sulfones with good results.