The first total synthesis of the antivirally active glycolipid cycloviracin B(1) (1) is described. The approach is based on a two-directional synthesis strategy which constructs the C(2)()-symmetrical macrodiolide core of the target by an efficient template-directed macrodilactonization reaction promoted by 2-chloro-1,3-dimethylimidazolinium chloride 14 as the activating agent. Attachment of the lateral fatty acid chains to the lactide core thus formed features not only one of the most advanced ligand-controlled addition reactions of a functionalized dialkyl zinc reagent to a polyfunctional aldehyde, but also a highly demanding Julia-Kocienski olefination of a tetrazolyl sulfone bearing electrophilic and base-labile beta-hydroxy ester motifs. By virtue of the flexibility of this synthesis plan, it was possible to prepare a series of macrodiolide cores differing only in the absolute stereochemistry at the branching points as well as a host of model compounds for the fatty acid appendices of cycloviracin. Comparison of these derivatives with the natural product allowed us to establish the as yet unknown absolute stereochemistry of 6 chiral centers of 1 as (3R,19S,25R,3'R,17'S,23'R). Thereby, the (13)C NMR shifts of the anomeric position of the beta-glycosides residing at those positions turned out to be excellent probes for the absolute configuration of the attached aglycones. The concise set of data thus obtained also makes clear that the proposed structure of the fattiviracins, a seemingly closely related family of glycoconjugates, is not matched by the published data. Finally, the biological activity of synthetic 1 and some of the key intermediates obtained en route to this natural product was investigated, showing that the entire construct is necessary for appreciable and selective antiviral activity.
Carbocyclic nucleosides are nucleoside analogues in which the furanosidic moiety has been replaced by a carbocycle. Several members of this family have been isolated from natural sources and include a 5-membered ring carbocycle. The aim of this review is to examine critically the different methodologies for the enantioselective construction of 3- to 6-membered rings, with a particular focus on 5-membered rings and their modifications. The procedures for bonding the heterocyclic moiety and the carbohydrate are treated separately. The methods for synthesising the carbocyclic moiety mainly focus on the construction of the cycle, although precise details about the functionalisation are provided in some cases. The selected methods aim to provide an overview of the synthesis of carbocycles related to the synthesis of carbocyclic nucleosides. The methods of synthesis of 5-membered rings are classified into two types: methods in which the cyclopentane ring is formed by ring closing reactions (C=C and C-C formation) and methods that start from preformed 5-membered rings, based mainly on cycloaddition reactions. With respect to the methods of synthesis of 3-, 4- and 6-membered ring carbocyclic nucleosides, a selection of the more relevant enantioselective procedures is presented in a systematic manner.
The synthesis of aziridine derivatives through metal-mediated nitrene addition reactions to olefins [Eq. (1)] has been extensively developed in the last decades; quantitative conversions as well as complete enantioselection have been already described. [1,2] However, in spite of the large number of reports related to the alkene aziridination reaction by this method and the synthetic interest of vinylaziridines, [3] only few have dealt with conjugated dienes as the substrate. Copper-, [4] manganese-, and ruthenium-based [5] catalysts have provided good yields of vinylaziridines formed by the exclusive aziridination of one C = C bond of the diene, although with the following limitations: 1) only symmetric dienes were employed and 2) selectivity, intended as cis/trans (or trans/cis) ratio, was low. These two drawbacks strongly prevent the synthetic application of this method.In fact, vinylaziridines are commonly synthesized by stoichiometric procedures based on nucleophilic intramolecular substitution. Thus, the Darzens-type reaction (Scheme 1, path a) is one of the oldest and most flexible methods for preparation of functional aziridine derivatives including vinylaziridines.
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