Total Synthesis of Branimycin: An Evolutionary Approach

Abstract

The first total synthesis of the macrolactone antibiotic branimycin (4) has been described. The key disconnection leads to a cis-dehydrodecalone core and a polyketide side chain which are connected via organometallic addition. The dehydrodecalone core was targeted via altogether five different approaches featuring various kinds of chiral elements and ring-closing methodology. In the end the most successful method starting from diepoxynaphthalene 109 was chosen to carry on with the synthesis. Thus the oxygen functions and carbon appendages were introduced via organometallic desymmetrization reactions to generate epoxy ketone 107, to which vinyl iodide 11 was added after conversion into the organolithium species. The synthesis was completed by introducing the ester side chain via Michael addition and subsequent macrolactonization.

Branimycins B and C, Antibiotics Produced by the Abyssal Actinobacterium Pseudonocardia carboxydivorans M-227

“…On the other hand, a detailed comparison of the NMR chemical shifts, multiplicities, and NOESY correlations of 2 and branimycin 7 also revealed the same relative configuration for both molecules, and the same absolute configuration could also be proposed on the basis of the similar magnitudes and positive values of their specific rotations ([α] 25 D +80, c 0.045, CHCl 3, for branimycin). 5 The absence of NOESY correlations between the H-18 protons and the methyl H-22 is in favor of an (R)-C-17 configuration as recently described for branimycin. 7 A molecular formula of C 24 H 36 O 9 was determined for compound 3 based on the existence of 24 signals in its 13 C NMR spectrum and ions detected in the HRESIMS spectrum corresponding to the proton and ammonium adducts.…”

“…3 Since then, there was a great interest in this new molecule, and a couple of organic syntheses have been developed. 4,5 Recently, the semisynthesis of branimycin derivatives has been reported in a patent, 6 demonstrating Avileś Canyon up to m depth. 10−13 One of these strains, Pseudonocardia carboxydivorans M-227, isolated at 3000 m depth in the water column, was further studied.…”

The Nargenicin Family of Oxa‐Bridged Macrolide Antibiotics

“…Several synthetic studies of these molecules have been attempted, which have resulted in the total synthesis of (+)‐18‐deoxynargencin A1 and branimycin A . Many synthetic approaches have focused on efficient routes to the oxa‐bridged octalin scaffold with the eventual goal of total synthesis of nargenicin A1 and these pathways are described in more detail below.…”

“…[15,18,19,23,25] Several synthetic studies of these molecules have been attempted, which have resulted in the total synthesis of (+ +)-18deoxynargencin A1 [26] and branimycin A. [22,27] Many synthetic approaches have focused on efficient routes to the oxabridged octalin scaffold with the eventual goal of total synthesis of nargenicin A1 and these pathways are described in more detail below.A ni mportant development in the study of the nargenicins wast he identification of the alpha subunit of DNA polymerase (also knowna sD naE) as its molecular target in Staphylococcus aureus. [28] This work, by scientists at Merck, led to ap atent detailing the activity of nargenicin derivatives against mycobacteria, in particular Mycobacterium tuberculosis.…”

Synthesis of polyhydroxylated decalins via two consecutive one-pot reactions: 1,4-addition/aldol reaction followed by RCM/syn-dihydroxylation

“…Indeed, some of the bicyclic carbasugars were proven to possess strong and selective anti-glycosidase activity [16–18]. The polyoxygenated bicyclic motif is also found in some members of the nargenicin antibiotics family [19–21]. …”