Stereoselective Total Syntheses of Herbicidin C and Aureonuclemycin through Late‐Stage Glycosylation

Nucleosides and their phosphates are involved in innumerable biochemical pathways, serving, for example, as building blocks for nucleic acids or as enzymatic cofactors. As such, it is not surprising that secondary metabolites have evolved that interfere with their elementary role in life. Many of these are nucleosides themselves that retain the canonical nucleobases, but feature more sophisticated carbohydrate residues than ribose. An important subclass are the so-called undecose nucleoside antibiotics, which include the herbicidins, represented by herbicidin A (1), B (2), C (3), and aureonuclemycin (4), as well as the tunicamycins (5) and hikizimycin (6) (Figure 1). All of these natural products contain a linear chain of 11 carbon atoms that can be incorporated in a variety of heterocyclic ring systems. The herbicidins were isolated from different strains of Streptomyces and exhibit several interesting biological activities. 5] For example, herbicidins A (1) and B (2) are efficient inhibitors of Xanthomas oryzae, a bacterium that causes leaf blight infection in rice crops. Furthermore, reduced seed germination and diminished algal growth, as well as selective toxicity towards dicotyledonous plants, but no toxicity against animals, was observed. Structurally, the herbicidins also show a number of intriguing characteristics. Their common undecose sugar moiety comprises a linear carbon chain that is folded into a tricyclic furano-pyrano-pyran skeleton, which includes nine stereogenic centers. Adenine, as the nucleobase, resides in a sterically congested concave position. In addition, the hemiketal at C-7 fuses the pyrano-pyran system in such a way that all of its substituents adopt axial orientations. Their individual members differ from each other through various methylation and esterification patterns. As a consequence of their structural beauty and potent biological activities, the undecose nucleoside antibiotics have attracted much attention from the synthetic community. However, despite considerable efforts, only one total synthesis of a herbicidin, namely herbicidin B (2) has been reported to date. The synthesis started with adenosine, with the purine base carried through the whole pathway. All other published approaches to the herbicidins opted for introduction of the nucleobase at a late stage, but have not yet reached their intended target. We now report a total synthesis of herbicidin C (3) and its hydrolysis product aureonuclemycin (4) which is based on a late-stage glycosylation strategy and marked by a high degree of stereoselectivity. Our retrosynthetic analysis of herbicidin C (3) is shown in Scheme 1. We reasoned that the challenging late-stage glycosylation could be stereochemically controlled by a neighboring benzoate at C-2, thereby yielding hemiacetal 7 as a logical precursor. This intermediate, in turn, could be traced back to C-glycoside 8, wherein C-7 and C-11 already possess the correct oxidation state. Further retrosynthetic simplification of the side chain would give ester 9, which could be ultimately derived from glucose (10). In the forward direction, glucose (10) was converted into the protected anhydro sugar 11, by combining a practical, large-scale synthesis for 1,6-anhydrohexopyranoses with a standard benzylation protocol (Scheme 2). Reaction of compound 11 with allyltrimethylsilane in the presence of a Lewis acid gave the known C-glycoside 12. This compound could be selectively debenzylated through a twostep protocol involving formation of the iodo ether (!13) Figure 1. Congeners of undecose nucleoside antibiotics.