Abstract
We have accomplished a 10-step (longest linear) total synthesis of nannocystin A on a four hundred milligram scale. The previously reported Kobayashi vinylogous Mukaiyama aldol reaction to connect C4 and C5 was unreproducible during the scaling up process. A more convenient and cost-efficient Keck asymmetric vinylogous aldol reaction was employed to improve this transformation.
Highlights
Marine myxobacteria are prolific producers of secondary metabolites owning unique structures and exhibiting multiple biological activities ranging from antibiotic to anticancer [1,2]
Nannocystin A (1) and its natural congener (2–6) (Figure 1) are myxobacterial secondary metabolites isolated by Hoepfner [7] and BrÖnstrup [8] independently from Nannocystis sp
They exhibit significant inhibitory activity against a broad variety of human cancer cells at nanomolar concentrations [7,8]. This anti-neoplastic activity is attributed to the binding affinity with elongation factor 1A [7]. Since this mechanism is shared by plitidepsin [9,10] which has recently been approved by the Australia Therapeutic Goods Administration for clinical use against multiple myeloma, it is obvious that nannocystins might be a promising lead for anti-cancer drug discovery
Summary
Marine myxobacteria are prolific producers of secondary metabolites owning unique structures and exhibiting multiple biological activities ranging from antibiotic to anticancer [1,2]. Nannocystin A (1) and its natural congener (2–6) (Figure 1) are myxobacterial secondary metabolites isolated by Hoepfner [7] and BrÖnstrup [8] independently from Nannocystis sp They exhibit significant inhibitory activity against a broad variety of human cancer cells at nanomolar concentrations [7,8]. This anti-neoplastic activity is attributed to the binding affinity with elongation factor 1A (eEF1A) [7] Since this mechanism is shared by plitidepsin [9,10] (isolated from the marine tunicate Aplidium albicans, Figure 1) which has recently been approved by the Australia Therapeutic Goods Administration for clinical use against multiple myeloma, it is obvious that nannocystins might be a promising lead for anti-cancer drug discovery
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